U.S. patent application number 17/670665 was filed with the patent office on 2022-09-29 for macrocyclic compounds for treating disease.
The applicant listed for this patent is Turning Point Therapeutics, Inc.. Invention is credited to Jingrong J. Cui, Wei Deng, Evan W. Rogers, Jane Ung, Jeffrey Whitten, Dayong Zhai, Han Zhang.
Application Number | 20220306652 17/670665 |
Document ID | / |
Family ID | 1000006394490 |
Filed Date | 2022-09-29 |
United States Patent
Application |
20220306652 |
Kind Code |
A1 |
Rogers; Evan W. ; et
al. |
September 29, 2022 |
MACROCYCLIC COMPOUNDS FOR TREATING DISEASE
Abstract
The present disclosure relates to certain macrocyclic
derivatives, pharmaceutical compositions containing them, and
methods of using them to treat disease, such as cancer.
Inventors: |
Rogers; Evan W.; (San Diego,
CA) ; Cui; Jingrong J.; (San Diego, CA) ;
Zhai; Dayong; (San Diego, CA) ; Zhang; Han;
(San Diego, CA) ; Ung; Jane; (San Diego, CA)
; Deng; Wei; (San Diego, CA) ; Whitten;
Jeffrey; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Turning Point Therapeutics, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
1000006394490 |
Appl. No.: |
17/670665 |
Filed: |
February 14, 2022 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16866983 |
May 5, 2020 |
11286265 |
|
|
17670665 |
|
|
|
|
16777717 |
Jan 30, 2020 |
10745416 |
|
|
16866983 |
|
|
|
|
PCT/US2018/066158 |
Dec 18, 2018 |
|
|
|
16777717 |
|
|
|
|
62779283 |
Dec 13, 2018 |
|
|
|
62727124 |
Sep 5, 2018 |
|
|
|
62607528 |
Dec 19, 2017 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 498/22 20130101;
A61P 35/00 20180101 |
International
Class: |
C07D 498/22 20060101
C07D498/22; A61P 35/00 20060101 A61P035/00 |
Claims
1. A compound of the formula I ##STR00170## wherein each L is
independently --C(R.sup.1)(R.sup.2)-- or X; with the proviso that,
when t is 1, then L is --C(R.sup.1)(R.sup.2)--; X is O, S, S(O) or
S(O).sub.2; each R.sup.1 and R.sup.2 is independently H, deuterium,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, or mono- or
bicyclic heteroaryl, --OR.sup.a, --OC(O)R.sup.a, --OC(O)R.sup.a,
--OC(O)NR.sup.aR.sup.b, --OS(O)R.sup.a, --OS(O).sub.2R.sup.a,
--SR.sup.a, --S(O)R.sup.a, --S(O).sub.2R.sup.a,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b,
--OS(O)NR.sup.aR.sup.b, --OS(O).sub.2NR.sup.aR.sup.b,
--NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.b, --NR.sup.aC(O)OR.sup.b,
--NR.sup.aC(O)NR.sup.aR.sup.b, --NR.sup.aS(O)R.sup.b,
--NR.sup.aS(O).sub.2R.sup.b, --NR.sup.aS(O)NR.sup.aR.sup.b,
--NR.sup.aS(O).sub.2NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --PR.sup.aR.sup.b, --P(O)R.sup.aR.sup.b,
--P(O).sub.2R.sup.aR.sup.b, --P(O)NR.sup.aR.sup.b,
--P(O).sub.2NR.sup.aR.sup.b, --P(O)OR.sup.a, --P(O).sub.2OR.sup.a,
--CN, or --NO.sub.2, or R.sup.1 and R.sup.2 taken together with the
carbon or carbons to which they are attached form a C.sub.3-C.sub.6
cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each
hydrogen atom in C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, mono- or
bicyclic heteroaryl, 4- to 6-membered heterocycloalkyl is
independently optionally substituted by deuterium, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, --OR.sup.e,
--OC(O)R.sup.e, --OC(O)NR.sup.eR.sup.f,
--OC(.dbd.N)NR.sup.eR.sup.f, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e,
--OS(O)NR.sup.eR.sup.f, --OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e,
--S(O)R.sup.e, --S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f, --NR.sup.cC(O)R,
--NR.sup.eC(O)OR.sup.f, --NR.sup.eC(O)NR.sup.eR.sup.f,
--NR.sup.eS(O)R.sup.f, --NR.sup.eS(O).sub.2R.sup.f,
--NR.sup.eS(O)NR.sup.eR.sup.f, --NR.sup.eS(O).sub.2NR.sup.eR.sup.f,
--C(O)R.sup.e, --C(O)OR.sup.e, --C(O)NR.sup.eR.sup.f,
--PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2; M is CR3 or N; M.sup.1 is CR4; each R.sup.3,
R.sup.4, and R.sup.5 is independently hydrogen, deuterium, halogen,
--OR.sup.c, --OC(O)R.sup.c, --OC(O)NR.sup.cR.sup.d,
--OC(.dbd.N)NR.sup.cR.sup.d, --OS(O)R.sup.c, --OS(O).sub.2R.sup.c,
--OS(O)NR.sup.cR.sup.d, --OS(O).sub.2NR.sup.cR.sup.d, --SR.sup.c,
--S(O)R.sup.c, --S(O).sub.2R.sup.c, --S(O)NR.sup.cR.sup.d,
--S(O).sub.2NR.sup.cR.sup.d, --NR.sup.cR.sup.d,
--NR.sup.cC(O)R.sup.d, --NR.sup.c'C(O)OR.sup.d,
--NR.sup.cC(O)NR.sup.cR.sup.d, --NR.sup.cC(.dbd.N)NR.sup.cR.sup.d,
--NR.sup.cS(O)R.sup.d, --NR.sup.cS(O).sub.2R.sup.d,
--NR.sup.cS(O)NR.sup.cR.sup.d, --NR.sup.cS(O).sub.2NR.sup.cR.sup.d,
--C(O)R.sup.c, --C(O)OR.sup.c, --C(O)NR.sup.cR.sup.d,
--C(.dbd.N)NR.sup.cR.sup.d, --PR.sup.cR.sup.d,
--P(O)R.sup.cR.sup.d, --P(O).sub.2R.sup.cR.sup.d,
--P(O)NR.sup.cR.sup.d, --P(O).sub.2NR.sup.cR.sup.d, --P(O)OR.sup.c,
--P(O).sub.2OR.sup.c, --CN, --NO.sub.2, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or mono- or bicyclic heteroaryl, or R.sup.4 and R.sup.5 taken
together with the ring to which they are attached form a
C.sub.5-C.sub.8 cycloalkyl, or a 5- to 8-membered heterocycloalkyl,
wherein each hydrogen atom in C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, mono- or bicyclic heteroaryl, C.sub.5-C.sub.8 cycloalkyl, or
5- to 8-membered heterocycloalkyl is independently optionally
substituted by deuterium, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, --OR.sup.e, --OC(O)R.sup.e,
--OC(O)NR.sup.eR.sup.f, --OC(.dbd.N)NR.sup.eR.sup.f,
--OS(O)R.sup.e, --OS(O).sub.2R.sup.e, --OS(O)NR.sup.eR.sup.f,
--OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e, --S(O)R.sup.e,
--S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.e(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2; R.sup.6 is H, deuterium, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.3-C.sub.6 cycloalkyl, 3- to 7-membered heterocycloalkyl,
C.sub.6-C.sub.10 aryl, or mono- or bicyclic heteroaryl, wherein
each hydrogen atom in C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, or mono- or
bicyclic heteroaryl is independently optionally substituted by
deuterium, halogen, C.sub.3-C.sub.6 cycloalkyl, or 5- to 7-membered
heterocycloalkyl, --OR.sup.e, --OC(O)R.sup.e,
--OC(O)NR.sup.eR.sup.f, --OC(.dbd.N)NR.sup.eR.sup.f,
--OS(O)R.sup.e, --OS(O).sub.2R.sup.e, --OS(O)NR.sup.eR.sup.f,
--OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e, --S(O)R.sup.e,
--S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.e(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2; R.sup.7 and R.sup.8 combine to form a
C.sub.3-C.sub.7 cycloalkyl, a 5- to 8-membered heterocycloalkyl,
C.sub.6-C.sub.10 aryl, or 5- to 7-membered heteroaryl; wherein each
hydrogen atom in C.sub.3-C.sub.7 cycloalkyl, a 5- to 8-membered
heterocycloalkyl, C.sub.6-C.sub.10 aryl, or 5- to 7-membered
heteroaryl is independently optionally substituted by deuterium,
halogen, --OR.sup.e, --OC(O)R.sup.e, --OC(O)NR.sup.eR.sup.f,
--OC(.dbd.N)NR.sup.eR.sup.f, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e,
--OS(O)NR.sup.eR.sup.f, --OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e,
--S(O)R.sup.e, --S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2; Y is O, S, NR.sup.9, or CR9R.sup.10; R.sup.9
and R.sup.10 are each independently H, deuterium, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to 7-membered
heterocycloalkyl, C.sub.6-C.sub.10 aryl, or mono- or bicyclic
heteroaryl, wherein each hydrogen atom in C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or mono- or bicyclic heteroaryl is optionally substituted by
a halogen, --OR.sup.e, --OC(O)R.sup.e, --OC(O)NR.sup.eR.sup.f,
--OC(.dbd.N)NR.sup.eR.sup.f, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e,
--OS(O)NR.sup.eR.sup.f, --OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e,
--S(O)R.sup.e, --S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, or
--P(O).sub.2OR.sup.e; each R.sup.a, R.sup.b, R.sup.c, R.sup.d,
R.sup.e, and R.sup.f is independently selected from the group
consisting of H, deuterium, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, 5- to
7-membered heteroaryl; each of Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4,
Z.sup.5, and Z.sup.6 is independently N, NH, C or CH; p is 1, 2, 3,
or 4; and t is 1, 2, 3, 4, or 5; or a pharmaceutically acceptable
salt thereof.
2. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein p is 1.
3. The compound of claim 2, or a pharmaceutically acceptable salt
thereof, wherein t is 3 or 4.
4. The compound of claim 1, having the formula III ##STR00171## or
a pharmaceutically acceptable salt thereof.
5. The compound of claim 4, or a pharmaceutically acceptable salt
thereof, wherein n is 2 or 3.
6. The compound of claim 1, having the formula IV or V ##STR00172##
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 5, or a pharmaceutically acceptable salt
thereof, wherein Y is O.
8. The compound of claim 7, or a pharmaceutically acceptable salt
thereof, wherein M is CR.sup.3.
9. The compound of claim 8, or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 is H, deuterium, C.sub.1-C.sub.6 alkyl or
halogen.
10. The compound of claim 7, or a pharmaceutically acceptable salt
thereof, wherein M is N.
11.-28. (canceled)
29. A method of treating cancer comprising administering to a
subject in need of such treatment an effective amount of at least
one compound of claim 1, or a pharmaceutically acceptable salt
thereof.
30. A method of inhibiting RET or SRC, comprising contacting a cell
comprising one or more of such kinases with an effective amount of
at least one compound of claim 1, or a pharmaceutically acceptable
salt thereof, and/or with at least one pharmaceutical composition
of the disclosure, wherein the contacting is in vitro, ex vivo, or
in vivo.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/866,983, filed on May 5, 2020, which is a
continuation of U.S. patent application Ser. No. 16/777,717, filed
on Jan. 30, 2020, which is a continuation which claims priority
under 35 U.S.C. .sctn. 120 to International Application No.
PCT/US2018/066158 filed on Dec. 18, 2018, which claims priority
under 35 U.S.C. .sctn. 119(e) to U.S. Provisional Application Ser.
No. 62/607,528 filed on Dec. 19, 2017, U.S. Provisional Application
Ser. No. 62/727,124 filed on Sep. 5, 2018, and U.S. Provisional
Application Ser. No. 62/779,283 filed on Dec. 13, 2018, the entire
disclosures of which are incorporated herein by reference.
TECHNICAL FIELD
[0002] The present disclosure relates to certain macrocyclic
derivatives, pharmaceutical compositions containing them, and
methods of using them to treat disease, such as cancer.
BACKGROUND
[0003] Protein kinases regulate various functions in the cell
including cell growth, proliferation and survival. Dysregulation of
protein kinases is often the cause of many solid malignancies
(Manning G. et al. Science. 2002, 298, 1912-1934). The use of
protein kinase inhibitors has led to substantial clinical benefit
in patients harboring oncogenic aberrations. More than thirty
protein kinase inhibitors have been approved for clinical treatment
of cancer (Berndt N. et al. Curr. Opin. Chem. Biol. 2017,
39:126-132). RET is a receptor tyrosine kinase that was initially
discovered in 1985 through transfection of NIH3T3 cells with human
lymphoma DNA (Takahashi, M. et al. Cell. 1985, 42:581-588.). RET is
expressed with its highest levels in early embryogenesis (during
which it has diverse roles in different tissues) and decreases to
relatively low levels in normal adult tissues Pachnis, V., et al.
Development 1993, 119, 1005-1017). RET plays a critical role in the
development of enteric nervous system and kidneys during
embryogenesis (Schuchardt, A. et al. Nature 1994, 367:380-383). RET
activation regulates the downstream signalling pathways
(RAS/MAPK/ERK, PI3K/AKT, and JAK-STAT etc.), leading to cellular
proliferation, migration, and differentiation (Mulligan, L M. Nat
Rev Cancer. 2014, 14(3):173-86).
[0004] Gain-of-function mutations of RET with constitutive
activation have been found in heritable and sporadic tumors
including activating point mutations within the full-length RET
protein or genomic rearrangements that produce chimeric RET
oncoproteins in the cytosol. The heritable oncogenic RET mutations
are found in multiple endocrine neoplasia type 2 (MEN2) including
medullary thyroid cancer (MTC) and familial MTC with more than 80
pathogenic variants spanning RET exons 5-16 reported (Mulligan, L
M. Nat Rev Cancer. 2014, 14(3):173-86). Among them, RET M918T and
RET A883F are found in 40-65% of sporadic MTC. The somatic
mutation, chimeric RET fusion oncoproteins have been identified in
sporadic tumors. The RET rearrangements are originally reported in
papillary thyroid cancers (PTCs) (Grieco, M. et al. Cell. 1990, 23;
60 (4):557-63.). The resulting fusion transcripts composed of the
3' end of RET kinase domain and the 5' end of separate partner
genes (CCDC6, NCOA4, TRIM24, TRIM33, PRKAR1A, GOLGA5, KTN1, ERC1,
MBD1, and TRIM27 etc.). RET fusions are identified in approximately
20%-40% of PTCs, and CCDC6-RET and NCOA4-RET are the most commonly
identified RET fusions in PTCs (Drilon A, et al. Nat Rev Clin
Oncol. 2017 Nov. 14. doi: 10.1038/nrclinonc.2017.175). RET gene
fusions are also found in approximately 1%-2% of non-small cell
lung cancer (NSCLC) (Gainor J F, Shaw A T. Oncologist. 2013,
18(7):865-75), and over 50% of RET fusions in NSCLC is KIF5B-RET,
representing the most frequent RET fusion form. However, the RET
inhibitors have relatively low response rates and short treatment
duration in the treatment of NSCLC patients with KIF5B-RET fusion
gene in multiple clinical trials (Drilon, A. Nat Rev Clin Oncol.
2017 Nov. 14. doi:10.1038/nrclinonc. 2017.175). It was reported
that the kinesin and kinase domains of KIF5B-RET act together to
establish an emergent microtubule and RAB-vesicle-dependent
RET-SRC-EGFR-FGFR signaling hub (Das T K and Cagan R L Cell Rep.
2017, 20(10):2368-2383). The inhibition of SRC kinase will have the
potential to stop the recruitment of multiple RTKs via the N
terminus of the KIF5B-RET fusion protein and the oncogenic
signaling to increase the therapeutic efficiency of RET inhibitors.
In addition, Src family tyrosine kinases regulate MTC cellular
proliferation in vitro and mediate growth signals by increasing DNA
synthesis and decreasing apoptosis (Liu Z, et al. J. Clin.
Endocrinol. Metab. 2004, 89, 3503-3509). Therefore, a dual
inhibitor of RET and SRC represents a highly desired therapeutic
intervention to maximally target abnormal RET signaling in
cancers.
SUMMARY
[0005] In one aspect, the disclosure relates to a compound of the
formula I
##STR00001##
[0006] wherein
[0007] L is independently --C(R.sup.1)(R.sup.2)-- or X;
[0008] X is --O--, --S--, --S(O)-- or --S(O).sub.2--;
[0009] each R.sup.1 and R.sup.2 is independently H, deuterium,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, or mono- or
bicyclic heteroaryl, --OR.sup.a, --OC(O)R.sup.a, --OC(O)R.sup.a,
--OC(O)NR.sup.aR.sup.b, --OS(O)R.sup.a, --OS(O).sub.2R.sup.a,
--SR.sup.a, --S(O)R.sup.a, --S(O).sub.2R.sup.a,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b,
--OS(O)NR.sup.aR.sup.b, --OS(O).sub.2NR.sup.aR.sup.b,
--NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.b, --NR.sup.aC(O)OR.sup.b,
--NR.sup.aC(O)NR.sup.aR.sup.b, --NR.sup.aS(O)R.sup.b,
--NR.sup.aS(O).sub.2R.sup.b, --NR.sup.aS(O)NR.sup.aR.sup.b,
--NR.sup.aS(O).sub.2NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --PR.sup.aR.sup.b, --P(O)R.sup.aR.sup.b,
--P(O).sub.2R.sup.aR.sup.b, --P(O)NR.sup.aR.sup.b,
--P(O).sub.2NR.sup.aR.sup.b, --P(O)OR.sup.a, --P(O).sub.2OR.sup.a,
--CN, or --NO.sub.2, or R.sup.1 and R.sup.2 taken together with the
carbon or carbons to which they are attached form a C.sub.3-C.sub.6
cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each
hydrogen atom in C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, mono- or
bicyclic heteroaryl, 4- to 6-membered heterocycloalkyl is
independently optionally substituted by deuterium, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, --OR.sup.e,
--OC(O)R.sup.e, --OC(O)NR.sup.eR.sup.f,
--OC(.dbd.N)NR.sup.eR.sup.f, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e,
--OS(O)NR.sup.eR.sup.f, --OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e,
--S(O)R.sup.e, --S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2;
[0010] M is CR.sup.3 or N;
[0011] M.sup.1 is CR.sup.4;
[0012] each R.sup.3, R.sup.4, and R.sup.5 is independently
hydrogen, deuterium, halogen, --OR.sup.c, --OC(O)R.sup.c,
--OC(O)NR.sup.eR.sup.d, --OC(.dbd.N)NR.sup.eR.sup.d,
--OS(O)R.sup.c, --OS(O).sub.2R.sup.c, --OS(O)NR.sup.eR.sup.d,
--OS(O).sub.2NR.sup.eR.sup.d, --SR.sup.c, --S(O)R.sup.c,
--S(O).sub.2R.sup.c, --S(O)NR.sup.eR.sup.d,
--S(O).sub.2NR.sup.eR.sup.d, --NR.sup.eR.sup.d,
--NR.sup.cC(O)R.sup.d, --NR.sup.c'C(O)OR.sup.d,
--NR.sup.cC(O)NR.sup.cR.sup.d, --NR.sup.cC(.dbd.N)NR.sup.cR.sup.d,
--NR.sup.cS(O)R.sup.d, --NR.sup.cS(O).sub.2R.sup.d,
--NR.sup.cS(O)NR.sup.cR.sup.d, --NR.sup.cS(O).sub.2NR.sup.cR.sup.d,
--C(O)R.sup.c, --C(O)OR.sup.c, --C(O)NR.sup.cR.sup.d,
--C(.dbd.N)NR.sup.cR.sup.d, --PR.sup.cR.sup.d,
--P(O)R.sup.cR.sup.d, --P(O).sub.2R.sup.cR.sup.d,
--P(O)NR.sup.cR.sup.d, --P(O).sub.2NR.sup.cR.sup.d, --P(O)OR.sup.c,
--P(O).sub.2OR.sup.c, --CN, --NO.sub.2, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or mono- or bicyclic heteroaryl, or R.sup.4 and R.sup.5 taken
together with the ring to which they are attached form a
C.sub.5-C.sub.8cycloalkyl, or a 5- to 8-membered heterocycloalkyl,
wherein each hydrogen atom in C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, mono- or bicyclic heteroaryl, C.sub.5-C.sub.8cycloalkyl, or
5- to 8-membered heterocycloalkyl is independently optionally
substituted by deuterium, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, --OR.sup.e, --OC(O)R.sup.e,
--OC(O)NR.sup.eR.sup.f, --OC(.dbd.N)NR.sup.eR.sup.f,
--OS(O)R.sup.e, --OS(O).sub.2R.sup.e, --OS(O)NR.sup.eR.sup.f,
--OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e, --S(O)R.sup.e,
--S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2;
[0013] R.sup.6 is H, deuterium, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom
in C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to 7-membered
heterocycloalkyl, C.sub.6-C.sub.10 aryl, or mono- or bicyclic
heteroaryl is independently optionally substituted by deuterium,
halogen, --OR.sup.e, --OC(O)R.sup.e, --OC(O)NR.sup.eR.sup.f,
--OC(.dbd.N)NR.sup.eR.sup.f, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e,
--OS(O)NR.sup.eR.sup.f, --OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e,
--S(O)R.sup.e, --S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2;
[0014] R.sup.7 and R.sup.8 combine to form a C.sub.3-C.sub.7
cycloalkyl, a 5- to 8-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in
C.sub.3-C.sub.7 cycloalkyl, a 5- to 8-membered heterocycloalkyl,
C.sub.6-C.sub.10 aryl, or 5- to 7-membered heteroaryl is
independently optionally substituted by deuterium, halogen,
--OR.sup.e, --OC(O)R.sup.e, --OC(O)NR.sup.eR.sup.f,
--OC(.dbd.N)NR.sup.eR.sup.f, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e,
--OS(O)NR.sup.eR.sup.f, --OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e,
--S(O)R.sup.e, --S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2;
[0015] Y is O, S, NR.sup.9, or CR.sup.9R.sup.10;
[0016] R.sup.9 and R.sup.10 are each independently H, deuterium,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, or mono- or
bicyclic heteroaryl, wherein each hydrogen atom in C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.3-C.sub.6 cycloalkyl, 3- to 7-membered heterocycloalkyl,
C.sub.6-C.sub.10 aryl, or mono- or bicyclic heteroaryl is
optionally substituted by a halogen, --OR.sup.e, --OC(O)R.sup.e,
--OC(O)NR.sup.eR.sup.f, --OC(.dbd.N)NR.sup.eR.sup.f,
--OS(O)R.sup.e, --OS(O).sub.2R.sup.e, --OS(O)NR.sup.eR.sup.f,
--OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e, --S(O)R.sup.e,
--S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, or
--P(O).sub.2OR.sup.e;
[0017] each R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e, and
R.sup.f is independently selected from the group consisting of H,
deuterium, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, 5- to
7-membered heteroaryl;
[0018] each of Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4, Z.sup.5, and
Z.sup.6 is independently N, NH, C or CH;
[0019] p is 1, 2, 3, or 4; and
[0020] t is 1, 2, 3, 4, or 5;
[0021] or a pharmaceutically acceptable salt thereof.
[0022] In another aspect, the disclosure relates to a compound of
the formula I
##STR00002##
[0023] wherein
[0024] L is independently --C(R.sup.1)(R.sup.2)-- or X;
[0025] X is O, S, S(O) or S(O).sub.2;
[0026] each R.sup.1 and R.sup.2 is independently H, deuterium,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, or mono- or
bicyclic heteroaryl, --OR.sup.a, --OC(O)R.sup.a, --OC(O)R.sup.a,
--OC(O)NR.sup.aR.sup.b, --OS(O)R.sup.a, --OS(O).sub.2R.sup.a,
--SR.sup.a, --S(O)R.sup.a, --S(O).sub.2R.sup.a,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b,
--OS(O)NR.sup.aR.sup.b, --OS(O).sub.2NR.sup.aR.sup.b,
--NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.b, --NR.sup.aC(O)OR.sup.b,
--NR.sup.aC(O)NR.sup.aR.sup.b, --NR.sup.aS(O)R.sup.b,
--NR.sup.aS(O).sub.2R.sup.b, --NR.sup.aS(O)NR.sup.aR.sup.b,
--NR.sup.aS(O).sub.2NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --PR.sup.aR.sup.b, --P(O)R.sup.aR.sup.b,
--P(O).sub.2R.sup.aR.sup.b, --P(O)NR.sup.aR.sup.b,
--P(O).sub.2NR.sup.aR.sup.b, --P(O)OR.sup.a, --P(O).sub.2OR.sup.a,
--CN, or --NO.sub.2, or R.sup.1 and R.sup.2 taken together with the
carbon or carbons to which they are attached form a C.sub.3-C.sub.6
cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each
hydrogen atom in C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, mono- or
bicyclic heteroaryl, 4- to 6-membered heterocycloalkyl is
independently optionally substituted by deuterium, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, --OR.sup.e,
--OC(O)R.sup.e, --OC(O)NR.sup.eR.sup.f,
--OC(.dbd.N)NR.sup.eR.sup.f, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e,
--OS(O)NR.sup.eR.sup.f, --OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e,
--S(O)R.sup.e, --S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.t, --NR.sup.eC(O)OR.sup.t,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2;
[0027] M is CR.sup.3 or N;
[0028] M.sup.1 is CR.sup.4;
[0029] each R.sup.3, R.sup.4, and R.sup.5 is independently
hydrogen, deuterium, halogen, --OR.sup.c, --OC(O)R.sup.c,
--OC(O)NR.sup.eR.sup.d, --OC(.dbd.N)NR.sup.eR.sup.d,
--OS(O)R.sup.c, --OS(O).sub.2R.sup.c, --OS(O)NR.sup.eR.sup.d,
--OS(O).sub.2NR.sup.eR.sup.d, --SR.sup.c, --S(O)R.sup.c,
--S(O).sub.2R.sup.c, --S(O)NR.sup.eR.sup.d,
--S(O).sub.2NR.sup.eR.sup.d, --NR.sup.eR.sup.d,
--NR.sup.cC(O)R.sup.d, --NR.sup.c'C(O)OR.sup.d,
--NR.sup.cC(O)NR.sup.cR.sup.d, --NR.sup.cC(.dbd.N)NR.sup.cR.sup.d,
--NR.sup.cS(O)R.sup.d, --NR.sup.cS(O).sub.2R.sup.d,
--NR.sup.cS(O)NR.sup.cR.sup.d, --NR.sup.cS(O).sub.2NR.sup.cR.sup.d,
--C(O)R.sup.c, --C(O)OR.sup.c, --C(O)NR.sup.cR.sup.d,
--C(.dbd.N)NR.sup.cR.sup.d, --PR.sup.cR.sup.d,
--P(O)R.sup.cR.sup.d, --P(O).sub.2R.sup.eR.sup.d,
--P(O)NR.sup.eR.sup.d, --P(O).sub.2NR.sup.eR.sup.d, --P(O)OR.sup.c,
--P(O).sub.2OR.sup.c, --CN, --NO.sub.2, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or mono- or bicyclic heteroaryl, or R.sup.4 and R.sup.5 taken
together with the ring to which they are attached form a
C.sub.5-C.sub.8cycloalkyl, or a 5- to 8-membered heterocycloalkyl,
wherein each hydrogen atom in C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, mono- or bicyclic heteroaryl, C.sub.5-C.sub.8cycloalkyl, or
5- to 8-membered heterocycloalkyl is independently optionally
substituted by deuterium, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, --OR.sup.e, --OC(O)R.sup.e,
--OC(O)NR.sup.eR.sup.f, --OC(.dbd.N)NR.sup.eR.sup.f,
--OS(O)R.sup.e, --OS(O).sub.2R.sup.e, --OS(O)NR.sup.eR.sup.f,
--OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e, --S(O)R.sup.e,
--S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2;
[0030] R.sup.6 is H, deuterium, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom
in C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to 7-membered
heterocycloalkyl, C.sub.6-C.sub.10 aryl, or mono- or bicyclic
heteroaryl is independently optionally substituted by deuterium,
halogen, C.sub.3-C.sub.6 cycloalkyl, or 5- to 7-membered
heterocycloalkyl, --OR.sup.e, --OC(O)R.sup.e,
--OC(O)NR.sup.eR.sup.f, --OC(.dbd.N)NR.sup.eR.sup.f,
--OS(O)R.sup.e, --OS(O).sub.2R.sup.e, --OS(O)NR.sup.eR.sup.f,
--OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e, --S(O)R.sup.e,
--S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.t,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2;
[0031] R.sup.7 and R.sup.8 combine to form a C.sub.3-C.sub.7
cycloalkyl, a 5- to 8-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in
C.sub.3-C.sub.7 cycloalkyl, a 5- to 8-membered heterocycloalkyl,
C.sub.6-C.sub.10 aryl, or 5- to 7-membered heteroaryl is
independently optionally substituted by deuterium, halogen,
--OR.sup.e, --OC(O)R.sup.e, --OC(O)NR.sup.eR.sup.f,
--OC(.dbd.N)NR.sup.eR.sup.f, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e,
--OS(O)NR.sup.eR.sup.f, --OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e,
--S(O)R.sup.e, --S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2;
[0032] Y is O, S, NR.sup.9, or CR.sup.9R.sup.10;
[0033] R.sup.9 and R.sup.10 are each independently H, deuterium,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, or mono- or
bicyclic heteroaryl, wherein each hydrogen atom in C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.3-C.sub.6 cycloalkyl, 3- to 7-membered heterocycloalkyl,
C.sub.6-C.sub.10 aryl, or mono- or bicyclic heteroaryl is
optionally substituted by a halogen, --OR.sup.e, --OC(O)R.sup.e,
--OC(O)NR.sup.eR.sup.f, --OC(.dbd.N)NR.sup.eR.sup.f,
--OS(O)R.sup.e, --OS(O).sub.2R.sup.e, --OS(O)NR.sup.eR.sup.f,
--OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e, --S(O)R.sup.e,
--S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, or
--P(O).sub.2OR.sup.e;
[0034] each R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e, and
R.sup.f is independently selected from the group consisting of H,
deuterium, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, 5- to
7-membered heteroaryl;
[0035] each of Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4, Z.sup.5, and
Z.sup.6 is independently N, NH, C or CH;
[0036] p is 1, 2, 3, or 4; and
[0037] t is 1, 2, 3, 4, or 5;
[0038] or a pharmaceutically acceptable salt thereof.
[0039] In another aspect, the disclosure relates to a compound or a
pharmaceutically acceptable salt thereof, having the formula II
##STR00003##
[0040] wherein
[0041] M is CR.sup.3 or N;
[0042] M.sup.1 is CR.sup.4;
[0043] X is O, S, S(O), or S(O).sub.2;
[0044] each R.sup.1 and R.sup.2 is independently H, deuterium,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.10 aryl,
--OR.sup.a, --SR.sup.a, --NR.sup.aR.sup.b, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b; wherein each hydrogen atom in
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl and C.sub.6-C.sub.10 aryl is
independently optionally substituted by deuterium, halogen, --OH,
--CN, --OC.sub.1-C.sub.6 alkyl, --NH.sub.2, --OC(O)C.sub.1-C.sub.6
alkyl, --OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(O)NH(C.sub.1-C.sub.6 alkyl), --OC(O)NH.sub.2,
--OC(.dbd.N)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl), --OC(.dbd.N)NH.sub.2,
--OS(O)C.sub.1-C.sub.6 alkyl, --OS(O).sub.2C.sub.1-C.sub.6 alkyl,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)C.sub.1-C.sub.6 alkyl, --NHC(O)NH.sub.2,
--NHC(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --NHC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --NHC(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)OC.sub.1-C.sub.6 alkyl, --NHC(O)OH, --N(C.sub.1-C.sub.6
alkyl)C(O)OH, --NHS(O)C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl, --NHS(O)NH.sub.2,
--NHS(O).sub.2NH.sub.2, --N(C.sub.1-C.sub.6 alkyl)S(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH.sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --NHS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --CO.sub.2H, --C(O)OC.sub.1-C.sub.6
alkyl, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --SC.sub.1-C.sub.6 alkyl,
--S(O)C.sub.1-C.sub.6 alkyl, --S(O).sub.2C.sub.1-C.sub.6 alkyl,
--S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --S(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --S(O)NH.sub.2,
--S(O).sub.2NH.sub.2, --OS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --OS(O)NH.sub.2, --OS(O).sub.2NH.sub.2, --P(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.3-C.sub.6
cycloalkyl, or 3- to 7-membered heterocycloalkyl;
[0045] R.sup.3, R.sup.4, and R.sup.5 are each independently H,
fluoro, chloro, bromo, C.sub.1-C.sub.6 alkyl, --OH, --CN,
--OC.sub.1-C.sub.6 alkyl, --NHC.sub.1-C.sub.6 alkyl,
--N(C.sub.1-C.sub.6 alkyl).sub.2 or --CF.sub.3;
[0046] R.sup.6 is H, C.sub.1-C.sub.6 alkyl or 3- to 7-membered
heterocycloalkyl, wherein each hydrogen atom in C.sub.1-C.sub.6
alkyl or 3- to 7-membered heterocycloalkyl is independently
optionally substituted by halogen, --OH, --CN, --OC.sub.1-C.sub.6
alkyl, --NH.sub.2, --NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, --CO.sub.2H, --C(O)OC.sub.1-C.sub.6 alkyl,
--C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.3-C.sub.6 cycloalkyl,
or monocyclic 5- to 7-membered heterocycloalkyl;
[0047] R.sup.7 and R.sup.8 combine to form a C.sub.3-C.sub.7
cycloalkyl, a 5- to 8-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in
C.sub.3-C.sub.7 cycloalkyl, a 5- to 8-membered heterocycloalkyl,
C.sub.6-C.sub.10 aryl, or 5- to 7-membered heteroaryl is
independently optionally substituted by deuterium, halogen, --OH,
--OC.sub.1-C.sub.6 alkyl, --OC(O)C.sub.1-C.sub.6 alkyl,
--OC(O)NH.sub.2, --OC(O)NH(C.sub.1-C.sub.6 alkyl),
--OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --OC(.dbd.N)NH.sub.2,
--OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl),
--OC(.dbd.N)N(C.sub.1-C.sub.6 alkyl).sub.2, --OS(O)C.sub.1-C.sub.6
alkyl, --OS(O).sub.2C.sub.1-C.sub.6 alkyl, --OS(O)NH.sub.2,
--OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --OS(O).sub.2NH.sub.2,
--OS(O).sub.2NH(C.sub.1-C.sub.6 alkyl),
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --SH,
--SC.sub.1-C.sub.6 alkyl, --S(O)C.sub.1-C.sub.6 alkyl,
--S(O).sub.2C.sub.1-C.sub.6 alkyl, --S(O)NH.sub.2,
--S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6
alkyl).sub.2, --S(O).sub.2NH.sub.2, --S(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --NH.sub.2,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)C.sub.1-C.sub.6 alkyl, --NHC(O)OH,
--NHC(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6 alkyl)C(O)OH,
--N(C.sub.1-C.sub.6 alkyl)C(O)OC.sub.1-C.sub.6 alkyl,
--NHC(O)NH.sub.2, --NHC(O)NH(C.sub.1-C.sub.6 alkyl),
--NHC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --NHS(O)C.sub.1-C.sub.6
alkyl, --N(C.sub.1-C.sub.6 alkyl)S(O)C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl, --NHS(O)NH.sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)S(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2NH.sub.2, --NHS(O).sub.2NH(C.sub.1-C.sub.6 alkyl),
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --C(O)OC.sub.1-C.sub.6 alkyl,
--C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --P(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)(C.sub.1-C.sub.6 alkyl).sub.2,
--P(O).sub.2(C.sub.1-C.sub.6 alkyl).sub.2, --P(O)NH.sub.2,
--P(O)NH(C.sub.1-C.sub.6 alkyl), --P(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --P(O).sub.2NH.sub.2, --P(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --P(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --P(O)OH,
--P(O)OC.sub.1-C.sub.6 alkyl, --P(O).sub.2OH,
--P(O).sub.2OC.sub.1-C.sub.6 alkyl, --CN, or --NO.sub.2;
[0048] Y is O, S, NR.sup.9, or CR.sup.9R.sup.10;
[0049] R.sup.9 and R.sup.10 are each independently H, deuterium,
halogen, or C.sub.1-C.sub.6 alkyl, wherein each hydrogen atom in
C.sub.1-C.sub.6 alkyl is optionally substituted by a halogen, --OH,
--OC.sub.1-C.sub.6 alkyl, --OC(O)C.sub.1-C.sub.6 alkyl,
--OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --OC(O)NH(C.sub.1-C.sub.6
alkyl), --OC(O)NH.sub.2, --OC(.dbd.N)N(C.sub.1-C.sub.6
alkyl).sub.2, --OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl),
--OC(.dbd.N)NH.sub.2, --OS(O)C.sub.1-C.sub.6 alkyl,
--OS(O).sub.2C.sub.1-C.sub.6 alkyl, --OS(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O)NH.sub.2,
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --OS(O).sub.2NH.sub.2,
--SH, --SC.sub.1-C.sub.6 alkyl, --S(O)C.sub.1-C.sub.6 alkyl,
--S(O).sub.2C.sub.1-C.sub.6 alkyl, --S(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O)NH.sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --S(O).sub.2NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl).sub.2, --NH(C.sub.1-C.sub.6 alkyl),
--NH.sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)C.sub.1-C.sub.6 alkyl,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6 alkyl)C(O)OH,
--NHC(O)OC.sub.1-C.sub.6 alkyl, --NHC(O)OH, --N(C.sub.1-C.sub.6
alkyl)C(O)N(C.sub.1C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --NHC(O)N(C.sub.1C.sub.6 alkyl).sub.2,
--NHC(O)NH(C.sub.1C.sub.6 alkyl), --NHC(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O)C.sub.1-C.sub.6 alkyl,
--NHS(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O)NH.sub.2, --NHS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH.sub.2,
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2NH.sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --C(O)OC.sub.1-C.sub.6 alkyl,
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --C(O)NH(C.sub.1-C.sub.6
alkyl), --C(O)NH.sub.2, --P(C.sub.1-C.sub.6 alkyl).sub.2,
--P(O)(C.sub.1-C.sub.6 alkyl).sub.2, --P(O).sub.2(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--P(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --P(O)OC.sub.1-C.sub.6
alkyl, or --P(O).sub.2OC.sub.1-C.sub.6 alkyl;
[0050] each of Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4, Z.sup.5, and
Z.sup.6 is independently N, NH, C or CH; and
[0051] n is 2 or 3.
[0052] In another aspect, the disclosure relates to a compound
selected from the group consisting of
##STR00004## ##STR00005##
[0053] wherein
[0054] M is CR.sup.3 or N;
[0055] M.sup.1 is CR.sup.4;
[0056] X is O, S, S(O), or S(O).sub.2;
[0057] R.sup.1 and R.sup.2 are each independently H, deuterium,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.10 aryl,
--OR.sup.a, --SR.sup.a, --NR.sup.aR.sup.b, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b; wherein each hydrogen atom in
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl and C.sub.6-C.sub.10 aryl is
independently optionally substituted by deuterium, halogen, --OH,
--CN, --OC.sub.1-C.sub.6 alkyl, --OC.sub.1-C.sub.6
alkyl(C.sub.6-C.sub.10 aryl), --NH.sub.2, --OC(O)C.sub.1-C.sub.6
alkyl, --OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(O)NH(C.sub.1-C.sub.6 alkyl), --OC(O)NH.sub.2,
--OC(.dbd.N)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl), --OC(.dbd.N)NH.sub.2,
--OS(O)C.sub.1-C.sub.6 alkyl, --OS(O).sub.2C.sub.1-C.sub.6 alkyl,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)C.sub.1-C.sub.6 alkyl, --NHC(O)NH.sub.2,
--NHC(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --NHC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --NHC(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)OC.sub.1-C.sub.6 alkyl, --NHC(O)OH, --N(C.sub.1-C.sub.6
alkyl)C(O)OH, --NHS(O)C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl, --NHS(O)NH.sub.2,
--NHS(O).sub.2NH.sub.2, --N(C.sub.1-C.sub.6 alkyl)S(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH.sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --NHS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --CO.sub.2H, --C(O)OC.sub.1-C.sub.6
alkyl, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --SC.sub.1-C.sub.6 alkyl,
--S(O)C.sub.1-C.sub.6 alkyl, --S(O).sub.2C.sub.1-C.sub.6 alkyl,
--S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --S(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --S(O)NH.sub.2,
--S(O).sub.2NH.sub.2, --OS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --OS(O)NH.sub.2, --OS(O).sub.2NH.sub.2, --P(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.3-C.sub.6
cycloalkyl, or 3- to 7-membered heterocycloalkyl;
[0058] R.sup.3, R.sup.4, and R.sup.5 are each independently H,
fluoro, chloro, bromo, C.sub.1-C.sub.6 alkyl, --OH, --CN,
--OC.sub.1-C.sub.6 alkyl, --NHC.sub.1-C.sub.6 alkyl,
--N(C.sub.1-C.sub.6 alkyl).sub.2 or --CF.sub.3;
[0059] R.sup.6 is H, C.sub.1-C.sub.6 alkyl or 3- to 7-membered
heterocycloalkyl, wherein each hydrogen atom in C.sub.1-C.sub.6
alkyl or 3- to 7-membered heterocycloalkyl is independently
optionally substituted by halogen, --OH, --CN, --OC.sub.1-C.sub.6
alkyl, --NH.sub.2, --NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, --CO.sub.2H, --C(O)OC.sub.1-C.sub.6 alkyl,
--C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.3-C.sub.6 cycloalkyl,
or monocyclic 5- to 7-membered heterocycloalkyl;
[0060] R.sup.7 and R.sup.8 combine to form a C.sub.3-C.sub.7
cycloalkyl, a 5- to 8-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in
C.sub.3-C.sub.7 cycloalkyl, a 5- to 8-membered heterocycloalkyl,
C.sub.6-C.sub.10 aryl, or 5- to 7-membered heteroaryl is
independently optionally substituted by deuterium, halogen, --OH,
--OC.sub.1-C.sub.6 alkyl, --OC(O)C.sub.1-C.sub.6 alkyl,
--OC(O)NH.sub.2, --OC(O)NH(C.sub.1-C.sub.6 alkyl),
--OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --OC(.dbd.N)NH.sub.2,
--OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl),
--OC(.dbd.N)N(C.sub.1-C.sub.6 alkyl).sub.2, --OS(O)C.sub.1-C.sub.6
alkyl, --OS(O).sub.2C.sub.1-C.sub.6 alkyl, --OS(O)NH.sub.2,
--OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --OS(O).sub.2NH.sub.2,
--OS(O).sub.2NH(C.sub.1-C.sub.6 alkyl),
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --SH,
--SC.sub.1-C.sub.6 alkyl, --S(O)C.sub.1-C.sub.6 alkyl,
--S(O).sub.2C.sub.1-C.sub.6 alkyl, --S(O)NH.sub.2,
--S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6
alkyl).sub.2, --S(O).sub.2NH.sub.2, --S(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --NH.sub.2,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)C.sub.1-C.sub.6 alkyl, --NHC(O)OH,
--NHC(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6 alkyl)C(O)OH,
--N(C.sub.1-C.sub.6 alkyl)C(O)OC.sub.1-C.sub.6 alkyl,
--NHC(O)NH.sub.2, --NHC(O)NH(C.sub.1-C.sub.6 alkyl),
--NHC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --NHS(O)C.sub.1-C.sub.6
alkyl, --N(C.sub.1-C.sub.6 alkyl)S(O)C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl, --NHS(O)NH.sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)S(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2NH.sub.2, --NHS(O).sub.2NH(C.sub.1-C.sub.6 alkyl),
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --C(O)OC.sub.1-C.sub.6 alkyl,
--C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --P(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)(C.sub.1-C.sub.6 alkyl).sub.2,
--P(O).sub.2(C.sub.1-C.sub.6 alkyl).sub.2, --P(O)NH.sub.2,
--P(O)NH(C.sub.1-C.sub.6 alkyl), --P(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --P(O).sub.2NH.sub.2, --P(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --P(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --P(O)OH,
--P(O)OC.sub.1-C.sub.6 alkyl, --P(O).sub.2OH,
--P(O).sub.2OC.sub.1-C.sub.6 alkyl, --CN, or --NO.sub.2;
[0061] Y is O, S, NR.sup.9, or CR.sup.9R.sup.10; and
[0062] R.sup.9 and R.sup.10 are each independently H, deuterium,
halogen, or C.sub.1-C.sub.6 alkyl, wherein each hydrogen atom in
C.sub.1-C.sub.6 alkyl is optionally substituted by a halogen, --OH,
--OC.sub.1-C.sub.6 alkyl, --OC(O)C.sub.1-C.sub.6 alkyl,
--OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --OC(O)NH(C.sub.1-C.sub.6
alkyl), --OC(O)NH.sub.2, --OC(.dbd.N)N(C.sub.1-C.sub.6
alkyl).sub.2, --OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl),
--OC(.dbd.N)NH.sub.2, --OS(O)C.sub.1-C.sub.6 alkyl,
--OS(O).sub.2C.sub.1-C.sub.6 alkyl, --OS(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O)NH.sub.2,
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --OS(O).sub.2NH.sub.2,
--SH, --SC.sub.1-C.sub.6 alkyl, --S(O)C.sub.1-C.sub.6 alkyl,
--S(O).sub.2C.sub.1-C.sub.6 alkyl, --S(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O)NH.sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --S(O).sub.2NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl).sub.2, --NH(C.sub.1-C.sub.6 alkyl),
--NH.sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)C.sub.1-C.sub.6 alkyl,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6 alkyl)C(O)OH,
--NHC(O)OC.sub.1-C.sub.6 alkyl, --NHC(O)OH, --N(C.sub.1-C.sub.6
alkyl)C(O)N(C.sub.1C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --NHC(O)N(C.sub.1C.sub.6 alkyl).sub.2,
--NHC(O)NH(C.sub.1C.sub.6 alkyl), --NHC(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O)C.sub.1-C.sub.6 alkyl,
--NHS(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O)NH.sub.2, --NHS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH.sub.2,
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2NH.sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --C(O)OC.sub.1-C.sub.6 alkyl,
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --C(O)NH(C.sub.1-C.sub.6
alkyl), --C(O)NH.sub.2, --P(C.sub.1-C.sub.6 alkyl).sub.2,
--P(O)(C.sub.1-C.sub.6 alkyl).sub.2, --P(O).sub.2(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--P(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --P(O)OC.sub.1-C.sub.6
alkyl, or --P(O).sub.2OC.sub.1-C.sub.6 alkyl.
[0063] Additional embodiments, features, and advantages of the
disclosure will be apparent from the following detailed description
and through practice of the disclosure. The compounds of the
present disclosure can be described as embodiments in any of the
following enumerated clauses. It will be understood that any of the
embodiments described herein can be used in connection with any
other embodiments described herein to the extent that the
embodiments do not contradict one another.
[0064] 1. A compound of the formula I
##STR00006##
[0065] wherein
[0066] L is independently --C(R.sup.1)(R.sup.2)-- or X;
[0067] X is --O--, --S--, --S(O)-- or --S(O).sub.2--;
[0068] each R.sup.1 and R.sup.2 is independently H, deuterium,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, or mono- or
bicyclic heteroaryl, --OR.sup.a, --OC(O)R.sup.a, --OC(O)R.sup.a,
--OC(O)NR.sup.aR.sup.b, --OS(O)R.sup.a, --OS(O).sub.2R.sup.a,
--SR.sup.a, --S(O)R.sup.a, --S(O).sub.2R.sup.a,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b,
--OS(O)NR.sup.aR.sup.b, --OS(O).sub.2NR.sup.aR.sup.b,
--NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.b, --NR.sup.aC(O)OR.sup.b,
--NR.sup.aC(O)NR.sup.aR.sup.b, --NR.sup.aS(O)R.sup.b,
--NR.sup.aS(O).sub.2R.sup.b, --NR.sup.aS(O)NR.sup.aR.sup.b,
--NR.sup.aS(O).sub.2NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --PR.sup.aR.sup.b, --P(O)R.sup.aR.sup.b,
--P(O).sub.2R.sup.aR.sup.b, --P(O)NR.sup.aR.sup.b,
--P(O).sub.2NR.sup.aR.sup.b, --P(O)OR.sup.a, --P(O).sub.2OR.sup.a,
--CN, or --NO.sub.2, or R.sup.1 and R.sup.2 taken together with the
carbon or carbons to which they are attached form a C.sub.3-C.sub.6
cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each
hydrogen atom in C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, mono- or
bicyclic heteroaryl, 4- to 6-membered heterocycloalkyl is
independently optionally substituted by deuterium, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, --OR.sup.e,
--OC(O)R.sup.e, --OC(O)NR.sup.eR.sup.f,
--OC(.dbd.N)NR.sup.eR.sup.f, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e,
--OS(O)NR.sup.eR.sup.f, --OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e,
--S(O)R.sup.e, --S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.t, --NR.sup.eC(O)OR.sup.t,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2;
[0069] M is CR.sup.3 or N;
[0070] M.sup.1 is CR.sup.4;
[0071] each R.sup.3, R.sup.4, and R.sup.5 is independently
hydrogen, deuterium, halogen, --OR.sup.c, --OC(O)R.sup.c,
--OC(O)NR.sup.cR.sup.d, --OC(.dbd.N)NR.sup.cR.sup.d,
--OS(O)R.sup.c, --OS(O).sub.2R.sup.c, --OS(O)NR.sup.cR.sup.d,
--OS(O).sub.2NR.sup.cR.sup.d, --SR.sup.c, --S(O)R.sup.c,
--S(O).sub.2R.sup.c, --S(O)NR.sup.cR.sup.d,
--S(O).sub.2NR.sup.cR.sup.d, --NR.sup.cR.sup.d,
--NR.sup.cC(O)R.sup.d, --NR.sup.c'C(O)OR.sup.d,
--NR.sup.cC(O)NR.sup.eR.sup.d, --NR.sup.eC(.dbd.N)NR.sup.eR.sup.d,
--NR.sup.cS(O)R.sup.d, --NR.sup.cS(O).sub.2R.sup.d,
--NR.sup.cS(O)NR.sup.eR.sup.d, --NR.sup.cS(O).sub.2NR.sup.eR.sup.d,
--C(O)R.sup.c, --C(O)OR.sup.c, --C(O)NR.sup.eR.sup.d,
--C(.dbd.N)NR.sup.eR.sup.d, --PR.sup.eR.sup.d,
--P(O)R.sup.eR.sup.d, --P(O).sub.2R.sup.cR.sup.d,
--P(O)NR.sup.cR.sup.d, --P(O).sub.2NR.sup.cR.sup.d, --P(O)OR.sup.c,
--P(O).sub.2OR.sup.c, --CN, --NO.sub.2, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or mono- or bicyclic heteroaryl, or R.sup.4 and R.sup.5 taken
together with the ring to which they are attached form a
C.sub.5-C.sub.8 cycloalkyl, or a 5- to 8-membered heterocycloalkyl,
wherein each hydrogen atom in C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, mono- or bicyclic heteroaryl, C.sub.5-C.sub.8 cycloalkyl, or
5- to 8-membered heterocycloalkyl is independently optionally
substituted by deuterium, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, --OR.sup.e, --OC(O)R.sup.e,
--OC(O)NR.sup.eR.sup.f, --OC(.dbd.N)NR.sup.eR.sup.f,
--OS(O)R.sup.e, --OS(O).sub.2R.sup.e, --OS(O)NR.sup.eR.sup.f,
--OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e, --S(O)R.sup.e,
--S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2;
[0072] R.sup.6 is H, deuterium, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom
in C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to 7-membered
heterocycloalkyl, C.sub.6-C.sub.10 aryl, or mono- or bicyclic
heteroaryl is independently optionally substituted by deuterium,
halogen, --OR.sup.e, --OC(O)R.sup.e, --OC(O)NR.sup.eR.sup.f,
--OC(.dbd.N)NR.sup.eR.sup.f, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e,
--OS(O)NR.sup.eR.sup.f, --OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e,
--S(O)R.sup.e, --S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.t, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.t,
--NR.sup.eS(O).sub.2R.sup.t, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2;
[0073] R.sup.7 and R.sup.8 combine to form a C.sub.3-C.sub.7
cycloalkyl, a 5- to 8-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in
C.sub.3-C.sub.7 cycloalkyl, a 5- to 8-membered heterocycloalkyl,
C.sub.6-C.sub.10 aryl, or 5- to 7-membered heteroaryl is
independently optionally substituted by deuterium, halogen,
--OR.sup.e, --OC(O)R.sup.e, --OC(O)NR.sup.eR.sup.f,
--OC(.dbd.N)NR.sup.eR.sup.f, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e,
--OS(O)NR.sup.eR.sup.f, --OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e,
--S(O)R.sup.e, --S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.t, --NR.sup.eC(O)OR.sup.t,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.t,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2;
[0074] Y is O, S, NR.sup.9, or CR.sup.9R.sup.10;
[0075] R.sup.9 and R.sup.10 are each independently H, deuterium,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, or mono- or
bicyclic heteroaryl, wherein each hydrogen atom in C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.3-C.sub.6 cycloalkyl, 3- to 7-membered heterocycloalkyl,
C.sub.6-C.sub.10 aryl, or mono- or bicyclic heteroaryl is
optionally substituted by a halogen, --OR.sup.e, --OC(O)R.sup.e,
--OC(O)NR.sup.eR.sup.f, --OC(.dbd.N)NR.sup.eR.sup.f,
--OS(O)R.sup.e, --OS(O).sub.2R.sup.e, --OS(O)NR.sup.eR.sup.f,
--OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e, --S(O)R.sup.e,
--S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.t, --NR.sup.eC(O)OR.sup.t,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.t,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, or
--P(O).sub.2OR.sup.e;
[0076] each R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e, and
R.sup.f is independently selected from the group consisting of H,
deuterium, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, 5- to
7-membered heteroaryl;
[0077] each of Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4, Z.sup.5, and
Z.sup.6 is independently N, NH, C or CH;
[0078] p is 1, 2, 3, or 4; and
[0079] t is 1, 2, 3, 4, or 5;
[0080] or a pharmaceutically acceptable salt thereof.
[0081] 1a. A compound of the formula I
##STR00007##
[0082] wherein
[0083] L is independently --C(R.sup.1)(R.sup.2)-- or X;
[0084] X is O, S, S(O) or S(O).sub.2;
[0085] each R.sup.1 and R.sup.2 is independently H, deuterium,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, or mono- or
bicyclic heteroaryl, --OR.sup.a, --OC(O)R.sup.a, --OC(O)R.sup.a,
--OC(O)NR.sup.aR.sup.b, --OS(O)R.sup.a, --OS(O).sub.2R.sup.a,
--SR.sup.a, --S(O)R.sup.a, --S(O).sub.2R.sup.a,
--S(O)NR.sup.aR.sup.b, --S(O).sub.2NR.sup.aR.sup.b,
--OS(O)NR.sup.aR.sup.b, --OS(O).sub.2NR.sup.aR.sup.b,
--NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.b, --NR.sup.aC(O)OR.sup.b,
--NR.sup.aC(O)NR.sup.aR.sup.b, --NR.sup.aS(O)R.sup.b,
--NR.sup.aS(O).sub.2R.sup.b, --NR.sup.aS(O)NR.sup.aR.sup.b,
--NR.sup.aS(O).sub.2NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --PR.sup.aR.sup.b, --P(O)R.sup.aR.sup.b,
--P(O).sub.2R.sup.aR.sup.b, --P(O)NR.sup.aR.sup.b,
--P(O).sub.2NR.sup.aR.sup.b, --P(O)OR.sup.a, --P(O).sub.2OR.sup.a,
--CN, or --NO.sub.2, or R.sup.1 and R.sup.2 taken together with the
carbon or carbons to which they are attached form a C.sub.3-C.sub.6
cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each
hydrogen atom in C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, mono- or
bicyclic heteroaryl, 4- to 6-membered heterocycloalkyl is
independently optionally substituted by deuterium, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, --OR.sup.e,
--OC(O)R.sup.e, --OC(O)NR.sup.eR.sup.f,
--OC(.dbd.N)NR.sup.eR.sup.f, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e,
--OS(O)NR.sup.eR.sup.f, --OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e,
--S(O)R.sup.e, --S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.t, --NR.sup.eC(O)OR.sup.t,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.t,
--NR.sup.eS(O).sub.2R.sup.t, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2;
[0086] M is CR.sup.3 or N;
[0087] M.sup.1 is CR.sup.4;
[0088] each R.sup.3, R.sup.4, and R.sup.5 is independently
hydrogen, deuterium, halogen, --OR.sup.c, --OC(O)R.sup.c,
--OC(O)NR.sup.cR.sup.d, --OC(.dbd.N)NR.sup.cR.sup.d,
--OS(O)R.sup.c, --OS(O).sub.2R.sup.c, --OS(O)NR.sup.cR.sup.d,
--OS(O).sub.2NR.sup.cR.sup.d, --SR.sup.c, --S(O)R.sup.c,
--S(O).sub.2R.sup.c, --S(O)NR.sup.cR.sup.d,
--S(O).sub.2NR.sup.cR.sup.d, --NR.sup.cR.sup.d,
--NR.sup.cC(O)R.sup.d, --NR.sup.c'C(O)OR.sup.d,
--NR.sup.cC(O)NR.sup.cR.sup.d, --NR.sup.cC(.dbd.N)NR.sup.cR.sup.d,
--NR.sup.cS(O)R.sup.d, --NR.sup.cS(O).sub.2R.sup.d,
--NR.sup.cS(O)NR.sup.cR.sup.d, --NR.sup.cS(O).sub.2NR.sup.cR.sup.d,
--C(O)R.sup.c, --C(O)OR.sup.c, --C(O)NR.sup.cR.sup.d,
--C(.dbd.N)NR.sup.cR.sup.d, --PR.sup.cR.sup.d,
--P(O)R.sup.cR.sup.d, --P(O).sub.2R.sup.eR.sup.d,
--P(O)NR.sup.eR.sup.d, --P(O).sub.2NR.sup.eR.sup.d, --P(O)OR.sup.c,
--P(O).sub.2OR.sup.c, --CN, --NO.sub.2, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or mono- or bicyclic heteroaryl, or R.sup.4 and R.sup.5 taken
together with the ring to which they are attached form a
C.sub.5-C.sub.8 cycloalkyl, or a 5- to 8-membered heterocycloalkyl,
wherein each hydrogen atom in C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, mono- or bicyclic heteroaryl, C.sub.5-C.sub.8 cycloalkyl, or
5- to 8-membered heterocycloalkyl is independently optionally
substituted by deuterium, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, --OR.sup.e, --OC(O)R.sup.e,
--OC(O)NR.sup.eR.sup.f, --OC(.dbd.N)NR.sup.eR.sup.f,
--OS(O)R.sup.e, --OS(O).sub.2R.sup.e, --OS(O)NR.sup.eR.sup.f,
--OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e, --S(O)R.sup.e,
--S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2;
[0089] R.sup.6 is H, deuterium, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom
in C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to 7-membered
heterocycloalkyl, C.sub.6-C.sub.10 aryl, or mono- or bicyclic
heteroaryl is independently optionally substituted by deuterium,
halogen, C.sub.3-C.sub.6 cycloalkyl, or 5- to 7-membered
heterocycloalkyl, --OR.sup.e, --OC(O)R.sup.e,
--OC(O)NR.sup.eR.sup.f, --OC(.dbd.N)NR.sup.eR.sup.f,
--OS(O)R.sup.e, --OS(O).sub.2R.sup.e, --OS(O)NR.sup.eR.sup.f,
--OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e, --S(O)R.sup.e,
--S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2;
[0090] R.sup.7 and R.sup.8 combine to form a C.sub.3-C.sub.7
cycloalkyl, a 5- to 8-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in
C.sub.3-C.sub.7 cycloalkyl, a 5- to 8-membered heterocycloalkyl,
C.sub.6-C.sub.10 aryl, or 5- to 7-membered heteroaryl is
independently optionally substituted by deuterium, halogen,
--OR.sup.e, --OC(O)R.sup.e, --OC(O)NR.sup.eR.sup.f,
--OC(.dbd.N)NR.sup.eR.sup.f, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e,
--OS(O)NR.sup.eR.sup.f, --OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e,
--S(O)R.sup.e, --S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2;
[0091] Y is O, S, NR.sup.9, or CR.sup.9R.sup.10;
[0092] R.sup.9 and R.sup.10 are each independently H, deuterium,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, or mono- or
bicyclic heteroaryl, wherein each hydrogen atom in C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.3-C.sub.6 cycloalkyl, 3- to 7-membered heterocycloalkyl,
C.sub.6-C.sub.10 aryl, or mono- or bicyclic heteroaryl is
optionally substituted by a halogen, --OR.sup.e, --OC(O)R.sup.e,
--OC(O)NR.sup.eR.sup.f, --OC(.dbd.N)NR.sup.eR.sup.f,
--OS(O)R.sup.e, --OS(O).sub.2R.sup.e, --OS(O)NR.sup.eR.sup.f,
--OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e, --S(O)R.sup.e,
--S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, or
--P(O).sub.2OR.sup.e;
[0093] each R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e, and
R.sup.f is independently selected from the group consisting of H,
deuterium, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, 5- to
7-membered heteroaryl;
[0094] each of Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4, Z.sup.5, and
Z.sup.6 is independently N, NH, C or CH;
[0095] p is 1, 2, 3, or 4; and
[0096] t is 1, 2, 3, 4, or 5;
[0097] or a pharmaceutically acceptable salt thereof.
[0098] 2. The compound of clause 1, or a pharmaceutically
acceptable salt thereof, wherein p is 1.
[0099] 3. The compound of clause 1 or 2, or a pharmaceutically
acceptable salt thereof, wherein t is 3.
[0100] 3a. The compound of clause 1 or 2, or a pharmaceutically
acceptable salt thereof, wherein t is 3 or 4.
[0101] 4. The compound of clause 1, or a pharmaceutically
acceptable salt thereof, having the formula II
##STR00008##
[0102] wherein
[0103] M is CR.sup.3 or N;
[0104] M.sup.1 is CR.sup.4;
[0105] X is O, S, S(O), or S(O).sub.2;
[0106] each R.sup.1 and R.sup.2 is independently H, deuterium,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.10 aryl,
--OR.sup.a, --SR.sup.a, --NR.sup.aR.sup.b, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b; wherein each hydrogen atom in
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl and C.sub.6-C.sub.10 aryl is
independently optionally substituted by deuterium, halogen, --OH,
--CN, --OC.sub.1-C.sub.6 alkyl, --NH.sub.2, --OC(O)C.sub.1-C.sub.6
alkyl, --OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(O)NH(C.sub.1-C.sub.6 alkyl), --OC(O)NH.sub.2,
--OC(.dbd.N)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl), --OC(.dbd.N)NH.sub.2,
--OS(O)C.sub.1-C.sub.6 alkyl, --OS(O).sub.2C.sub.1-C.sub.6 alkyl,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)C.sub.1-C.sub.6 alkyl, --NHC(O)NH.sub.2,
--NHC(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --NHC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --NHC(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)OC.sub.1-C.sub.6 alkyl, --NHC(O)OH, --N(C.sub.1-C.sub.6
alkyl)C(O)OH, --NHS(O)C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl, --NHS(O)NH.sub.2,
--NHS(O).sub.2NH.sub.2, --N(C.sub.1-C.sub.6 alkyl)S(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH.sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --NHS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --CO.sub.2H, --C(O)OC.sub.1-C.sub.6
alkyl, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --SC.sub.1-C.sub.6 alkyl,
--S(O)C.sub.1-C.sub.6 alkyl, --S(O).sub.2C.sub.1-C.sub.6 alkyl,
--S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --S(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --S(O)NH.sub.2,
--S(O).sub.2NH.sub.2, --OS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --OS(O)NH.sub.2, --OS(O).sub.2NH.sub.2, --P(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.3-C.sub.6
cycloalkyl, or 3- to 7-membered heterocycloalkyl;
[0107] R.sup.3, R.sup.4, and R.sup.5 are each independently H,
fluoro, chloro, bromo, C.sub.1-C.sub.6 alkyl, --OH, --CN,
--OC.sub.1-C.sub.6 alkyl, --NHC.sub.1-C.sub.6 alkyl,
--N(C.sub.1-C.sub.6 alkyl).sub.2 or --CF.sub.3;
[0108] R.sup.6 is H, C.sub.1-C.sub.6 alkyl or 3- to 7-membered
heterocycloalkyl, wherein each hydrogen atom in C.sub.1-C.sub.6
alkyl or 3- to 7-membered heterocycloalkyl is independently
optionally substituted by halogen, --OH, --CN, --OC.sub.1-C.sub.6
alkyl, --NH.sub.2, --NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, --CO.sub.2H, --C(O)OC.sub.1-C.sub.6 alkyl,
--C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.3-C.sub.6 cycloalkyl,
or monocyclic 5- to 7-membered heterocycloalkyl;
[0109] R.sup.7 and R.sup.8 combine to form a C.sub.3-C.sub.7
cycloalkyl, a 5- to 8-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in
C.sub.3-C.sub.7 cycloalkyl, a 5- to 8-membered heterocycloalkyl,
C.sub.6-C.sub.10 aryl, or 5- to 7-membered heteroaryl is
independently optionally substituted by deuterium, halogen, --OH,
--OC.sub.1-C.sub.6 alkyl, --OC(O)C.sub.1-C.sub.6 alkyl,
--OC(O)NH.sub.2, --OC(O)NH(C.sub.1-C.sub.6 alkyl),
--OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --OC(.dbd.N)NH.sub.2,
--OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl),
--OC(.dbd.N)N(C.sub.1-C.sub.6 alkyl).sub.2, --OS(O)C.sub.1-C.sub.6
alkyl, --OS(O).sub.2C.sub.1-C.sub.6 alkyl, --OS(O)NH.sub.2,
--OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --OS(O).sub.2NH.sub.2,
--OS(O).sub.2NH(C.sub.1-C.sub.6 alkyl),
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --SH,
--SC.sub.1-C.sub.6 alkyl, --S(O)C.sub.1-C.sub.6 alkyl,
--S(O).sub.2C.sub.1-C.sub.6 alkyl, --S(O)NH.sub.2,
--S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6
alkyl).sub.2, --S(O).sub.2NH.sub.2, --S(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --NH.sub.2,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)C.sub.1-C.sub.6 alkyl, --NHC(O)OH,
--NHC(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6 alkyl)C(O)OH,
--N(C.sub.1-C.sub.6 alkyl)C(O)OC.sub.1-C.sub.6 alkyl,
--NHC(O)NH.sub.2, --NHC(O)NH(C.sub.1-C.sub.6 alkyl),
--NHC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --NHS(O)C.sub.1-C.sub.6
alkyl, --N(C.sub.1-C.sub.6 alkyl)S(O)C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl, --NHS(O)NH.sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)S(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2NH.sub.2, --NHS(O).sub.2NH(C.sub.1-C.sub.6 alkyl),
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --C(O)OC.sub.1-C.sub.6 alkyl,
--C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --P(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)(C.sub.1-C.sub.6 alkyl).sub.2,
--P(O).sub.2(C.sub.1-C.sub.6 alkyl).sub.2, --P(O)NH.sub.2,
--P(O)NH(C.sub.1-C.sub.6 alkyl), --P(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --P(O).sub.2NH.sub.2, --P(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --P(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --P(O)OH,
--P(O)OC.sub.1-C.sub.6 alkyl, --P(O).sub.2OH,
--P(O).sub.2OC.sub.1-C.sub.6 alkyl, --CN, or --NO.sub.2;
[0110] Y is O, S, NR.sup.9, or CR.sup.9R.sup.10;
[0111] R.sup.9 and R.sup.10 are each independently H, deuterium,
halogen, or C.sub.1-C.sub.6 alkyl, wherein each hydrogen atom in
C.sub.1-C.sub.6 alkyl is optionally substituted by a halogen, --OH,
--OC.sub.1-C.sub.6 alkyl, --OC(O)C.sub.1-C.sub.6 alkyl,
--OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --OC(O)NH(C.sub.1-C.sub.6
alkyl), --OC(O)NH.sub.2, --OC(.dbd.N)N(C.sub.1-C.sub.6
alkyl).sub.2, --OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl),
--OC(.dbd.N)NH.sub.2, --OS(O)C.sub.1-C.sub.6 alkyl,
--OS(O).sub.2C.sub.1-C.sub.6 alkyl, --OS(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O)NH.sub.2,
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --OS(O).sub.2NH.sub.2,
--SH, --SC.sub.1-C.sub.6 alkyl, --S(O)C.sub.1-C.sub.6 alkyl,
--S(O).sub.2C.sub.1-C.sub.6 alkyl, --S(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O)NH.sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --S(O).sub.2NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl).sub.2, --NH(C.sub.1-C.sub.6 alkyl),
--NH.sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)C.sub.1-C.sub.6 alkyl,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6 alkyl)C(O)OH,
--NHC(O)OC.sub.1-C.sub.6 alkyl, --NHC(O)OH, --N(C.sub.1-C.sub.6
alkyl)C(O)N(C.sub.1C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --NHC(O)N(C.sub.1C.sub.6 alkyl).sub.2,
--NHC(O)NH(C.sub.1C.sub.6 alkyl), --NHC(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O)C.sub.1-C.sub.6 alkyl,
--NHS(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O)NH.sub.2, --NHS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH.sub.2,
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2NH.sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --C(O)OC.sub.1-C.sub.6 alkyl,
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --C(O)NH(C.sub.1-C.sub.6
alkyl), --C(O)NH.sub.2, --P(C.sub.1-C.sub.6 alkyl).sub.2,
--P(O)(C.sub.1-C.sub.6 alkyl).sub.2, --P(O).sub.2(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--P(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --P(O)OC.sub.1-C.sub.6
alkyl, or --P(O).sub.2OC.sub.1-C.sub.6 alkyl;
[0112] each of Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4, Z.sup.5, and
Z.sup.6 is independently N, NH, C or CH; and
[0113] n is 2 or 3.
[0114] 5. The compound of any of the preceding clause, having the
formula III
##STR00009##
[0115] or a pharmaceutically acceptable salt thereof.
[0116] 6. The compound of clause 4 or 5, or a pharmaceutically
acceptable salt thereof, wherein n is 2.
[0117] 6a. The compound of clause 4 or 5, or a pharmaceutically
acceptable salt thereof, wherein n is 2 or 3.
[0118] 7. The compound of any one of the preceding clauses, having
the formula IV
##STR00010##
[0119] or a pharmaceutically acceptable salt thereof.
[0120] 7a. The compound of any one of the preceding clauses, having
the formula IV or V
##STR00011##
[0121] or a pharmaceutically acceptable salt thereof.
[0122] 8. The compound of any one of the preceding clauses, or a
pharmaceutically acceptable salt thereof, wherein Y is O.
[0123] 9. The compound of any one of the preceding clauses, or a
pharmaceutically acceptable salt thereof, wherein M is
CR.sup.3.
[0124] 10. The compound of any one of the preceding clauses, or a
pharmaceutically acceptable salt thereof, wherein R.sup.3 is H,
deuterium, C.sub.1-C.sub.6 alkyl or halogen.
[0125] 11. The compound of any one of the preceding clauses, or a
pharmaceutically acceptable salt thereof, wherein R.sup.3 is H or
F.
[0126] 12. The compound of any one of clauses 1 to 8, or a
pharmaceutically acceptable salt thereof, wherein M is N.
[0127] 13. The compound of any one of the preceding clauses, or a
pharmaceutically acceptable salt thereof, wherein M.sup.1 is
CR.sup.4.
[0128] 14. The compound of any one of the preceding clauses, or a
pharmaceutically acceptable salt thereof, wherein R.sup.4 is H,
deuterium, C.sub.1-C.sub.6 alkyl or halogen.
[0129] 15. The compound of any one of the preceding clauses, or a
pharmaceutically acceptable salt thereof, wherein R.sup.4 is H or
Cl.
[0130] 16. The compound of any one of the preceding clauses, or a
pharmaceutically acceptable salt thereof, wherein R.sup.5 is F.
[0131] 17. The compound of any one of the preceding clauses, or a
pharmaceutically acceptable salt thereof, wherein R.sup.2 is H.
[0132] 17a. The compound of any one of the preceding clauses, or a
pharmaceutically acceptable salt thereof, wherein at least one of
R.sup.2 is H.
[0133] 18. The compound of any one of the preceding clauses, or a
pharmaceutically acceptable salt thereof, wherein R.sup.1 is H.
[0134] 18a. The compound of any one of the preceding clauses, or a
pharmaceutically acceptable salt thereof, wherein at least one of
R.sup.1 is H.
[0135] 19. The compound of any one of clauses 1 to 17, or a
pharmaceutically acceptable salt thereof, wherein R.sup.1 is
C.sub.1-C.sub.6 alkyl.
[0136] 19a. The compound of any one of clauses 1 to 17, or a
pharmaceutically acceptable salt thereof, wherein at least one of
R.sup.1 is C.sub.1-C.sub.6 alkyl.
[0137] 20. The compound of any one of clauses 1 to 17, or a
pharmaceutically acceptable salt thereof, wherein R.sup.1 is H, and
R.sup.2 is C.sub.1-C.sub.6 alkyl.
[0138] 20a. The compound of any one of clauses 1 to 16, or a
pharmaceutically acceptable salt thereof, wherein R.sup.1 is H, and
R.sup.2 is C.sub.1-C.sub.6 alkyl; or R.sup.1 is C.sub.1-C.sub.6
alkyl, and R.sup.2 is H; or R.sup.1 is H or C.sub.1-C.sub.6 alkyl,
and R.sup.2 is H; or R.sup.1 is H, and R.sup.2 is C.sub.3-C.sub.7
cycloalkyl; or R.sup.1 is C.sub.3-C.sub.7 cycloalkyl, and R.sup.2
is H; or wherein one of R.sup.1 is C.sub.1-C.sub.6 alkyl, any other
R.sup.1, when present, is H, and any R.sup.2, when present, is
H.
[0139] 21. The compound of any one of the preceding clauses, or a
pharmaceutically acceptable salt thereof, wherein R.sup.7 and
R.sup.8 combine to form a 5- or 6-membered cycloalkyl, wherein each
hydrogen atom in the 5- or 6-membered cycloalkyl is independently
optionally substituted by deuterium, halogen, --OH, --CN,
--OC.sub.1-C.sub.6 alkyl, --OC.sub.1-C.sub.6 alkyl(C.sub.6-C.sub.10
aryl), --NH.sub.2, --OC(O)C.sub.1-C.sub.6 alkyl,
--OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --OC(O)NH(C.sub.1-C.sub.6
alkyl), --OC(O)NH.sub.2, --OC(.dbd.N)N(C.sub.1-C.sub.6
alkyl).sub.2, --OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl),
--OC(.dbd.N)NH.sub.2, --OS(O)C.sub.1-C.sub.6 alkyl,
--OS(O).sub.2C.sub.1-C.sub.6 alkyl, --NH(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl).sub.2, --NHC(O)C.sub.1-C.sub.6 alkyl,
--N(C.sub.1-C.sub.6 alkyl)C(O)C.sub.1-C.sub.6 alkyl,
--NHC(O)NH.sub.2, --NHC(O)NH(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl)C(O)NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --NHC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --NHC(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)OC.sub.1-C.sub.6 alkyl, --NHC(O)OH, --N(C.sub.1-C.sub.6
alkyl)C(O)OH, --NHS(O)C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl, --NHS(O)NH.sub.2,
--NHS(O).sub.2NH.sub.2, --N(C.sub.1-C.sub.6 alkyl)S(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH.sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --NHS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --CO.sub.2H, --C(O)OC.sub.1-C.sub.6
alkyl, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --SC.sub.1-C.sub.6 alkyl,
--S(O)C.sub.1-C.sub.6 alkyl, --S(O).sub.2C.sub.1-C.sub.6 alkyl,
--S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --S(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --S(O)NH.sub.2,
--S(O).sub.2NH.sub.2, --OS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --OS(O)NH.sub.2, --OS(O).sub.2NH.sub.2, --P(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.3-C.sub.6
cycloalkyl, or 3- to 7-membered heterocycloalkyl.
[0140] 21a. The compound of any one of the preceding clauses, or a
pharmaceutically acceptable salt thereof, wherein R.sup.7 and
R.sup.8 combine to form a 4-, 5- or 6-membered cycloalkyl, wherein
each hydrogen atom in the 5- or 6-membered cycloalkyl is
independently optionally substituted by deuterium, halogen, --OH,
--CN, --OC.sub.1-C.sub.6 alkyl, --OC.sub.1-C.sub.6
alkyl(C.sub.6-C.sub.10 aryl), --NH.sub.2, --OC(O)C.sub.1-C.sub.6
alkyl, --OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(O)NH(C.sub.1-C.sub.6 alkyl), --OC(O)NH.sub.2,
--OC(.dbd.N)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl), --OC(.dbd.N)NH.sub.2,
--OS(O)C.sub.1-C.sub.6 alkyl, --OS(O).sub.2C.sub.1-C.sub.6 alkyl,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)C.sub.1-C.sub.6 alkyl, --NHC(O)NH.sub.2,
--NHC(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --NHC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --NHC(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)OC.sub.1-C.sub.6 alkyl, --NHC(O)OH, --N(C.sub.1-C.sub.6
alkyl)C(O)OH, --NHS(O)C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl, --NHS(O)NH.sub.2,
--NHS(O).sub.2NH.sub.2, --N(C.sub.1-C.sub.6 alkyl)S(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH.sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --NHS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --CO.sub.2H, --C(O)OC.sub.1-C.sub.6
alkyl, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --SC.sub.1-C.sub.6 alkyl,
--S(O)C.sub.1-C.sub.6 alkyl, --S(O).sub.2C.sub.1-C.sub.6 alkyl,
--S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --S(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --S(O)NH.sub.2,
--S(O).sub.2NH.sub.2, --OS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --OS(O)NH.sub.2, --OS(O).sub.2NH.sub.2, --P(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.3-C.sub.6
cycloalkyl, or 3- to 7-membered heterocycloalkyl.
[0141] 22. The compound of any one of clauses 1 to 20, or a
pharmaceutically acceptable salt thereof, wherein R.sup.7 and
R.sup.8 combine to form a 3-, 4-, 5- or 6-membered
heterocycloalkyl, wherein each hydrogen atom in the 3-, 4-, 5- or
6-membered heterocycloalkyl is independently optionally substituted
by deuterium, halogen, --OH, --CN, --OC.sub.1-C.sub.6 alkyl,
--OC.sub.1-C.sub.6 alkyl(C.sub.6-C.sub.10 aryl), --NH.sub.2,
--OC(O)C.sub.1-C.sub.6 alkyl, --OC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --OC(O)NH(C.sub.1-C.sub.6 alkyl), --OC(O)NH.sub.2,
--OC(.dbd.N)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl), --OC(.dbd.N)NH.sub.2,
--OS(O)C.sub.1-C.sub.6 alkyl, --OS(O).sub.2C.sub.1-C.sub.6 alkyl,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)C.sub.1-C.sub.6 alkyl, --NHC(O)NH.sub.2,
--NHC(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --NHC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --NHC(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)OC.sub.1-C.sub.6 alkyl, --NHC(O)OH, --N(C.sub.1-C.sub.6
alkyl)C(O)OH, --NHS(O)C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl, --NHS(O)NH.sub.2,
--NHS(O).sub.2NH.sub.2, --N(C.sub.1-C.sub.6 alkyl)S(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH.sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --NHS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --CO.sub.2H, --C(O)OC.sub.1-C.sub.6
alkyl, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --SC.sub.1-C.sub.6 alkyl,
--S(O)C.sub.1-C.sub.6 alkyl, --S(O).sub.2C.sub.1-C.sub.6 alkyl,
--S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --S(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --S(O)NH.sub.2,
--S(O).sub.2NH.sub.2, --OS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --OS(O)NH.sub.2, --OS(O).sub.2NH.sub.2, --P(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.3-C.sub.6
cycloalkyl, or 3- to 7-membered heterocycloalkyl.
[0142] 23. The compound of clause 22, or a pharmaceutically
acceptable salt thereof, wherein R.sup.7 and R.sup.8 combine to
form a tetrahydrofuran ring.
[0143] 24. The compound of clause 21, or a pharmaceutically
acceptable salt thereof, wherein R.sup.7 and R.sup.8 combine to
form a cyclopentane ring.
[0144] 24a. The compound of clause 21 or 21a, or a pharmaceutically
acceptable salt thereof, wherein R.sup.7 and R.sup.8 combine to
form a cyclobutane ring, cyclopentane ring, or cyclohexane
ring.
[0145] 25. The compound of clause 1, or a pharmaceutically
acceptable salt thereof, selected form the group consisting of
##STR00012## ##STR00013## ##STR00014## ##STR00015##
##STR00016##
[0146] wherein
[0147] M is CR.sup.3 or N;
[0148] M.sup.1 is CR.sup.4;
[0149] X is O, S, S(O), or S(O).sub.2;
[0150] R.sup.1 and R.sup.2 are each independently H, deuterium,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.10 aryl,
--OR.sup.a, --SR.sup.a, --NR.sup.aR.sup.b, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b; wherein each hydrogen atom in
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl and C.sub.6-C.sub.10 aryl is
independently optionally substituted by deuterium, halogen, --OH,
--CN, --OC.sub.1-C.sub.6 alkyl, --OC.sub.1-C.sub.6
alkyl(C.sub.6-C.sub.10 aryl), --NH.sub.2, --OC(O)C.sub.1-C.sub.6
alkyl, --OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(O)NH(C.sub.1-C.sub.6 alkyl), --OC(O)NH.sub.2,
--OC(.dbd.N)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl), --OC(.dbd.N)NH.sub.2,
--OS(O)C.sub.1-C.sub.6 alkyl, --OS(O).sub.2C.sub.1-C.sub.6 alkyl,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)C.sub.1-C.sub.6 alkyl, --NHC(O)NH.sub.2,
--NHC(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --NHC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --NHC(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)OC.sub.1-C.sub.6 alkyl, --NHC(O)OH, --N(C.sub.1-C.sub.6
alkyl)C(O)OH, --NHS(O)C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl, --NHS(O)NH.sub.2,
--NHS(O).sub.2NH.sub.2, --N(C.sub.1-C.sub.6 alkyl)S(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH.sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --NHS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --CO.sub.2H, --C(O)OC.sub.1-C.sub.6
alkyl, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --SC.sub.1-C.sub.6 alkyl,
--S(O)C.sub.1-C.sub.6 alkyl, --S(O).sub.2C.sub.1-C.sub.6 alkyl,
--S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --S(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --S(O)NH.sub.2,
--S(O).sub.2NH.sub.2, --OS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --OS(O)NH.sub.2, --OS(O).sub.2NH.sub.2, --P(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.3-C.sub.6
cycloalkyl, or 3- to 7-membered heterocycloalkyl;
[0151] R.sup.3, R.sup.4, and R.sup.5 are each independently H,
fluoro, chloro, bromo, C.sub.1-C.sub.6 alkyl, --OH, --CN,
--OC.sub.1-C.sub.6 alkyl, --NHC.sub.1-C.sub.6 alkyl,
--N(C.sub.1-C.sub.6 alkyl).sub.2 or --CF.sub.3;
[0152] R.sup.6 is H, C.sub.1-C.sub.6 alkyl or 3- to 7-membered
heterocycloalkyl, wherein each hydrogen atom in C.sub.1-C.sub.6
alkyl or 3- to 7-membered heterocycloalkyl is independently
optionally substituted by halogen, --OH, --CN, --OC.sub.1-C.sub.6
alkyl, --NH.sub.2, --NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, --CO.sub.2H, --C(O)OC.sub.1-C.sub.6 alkyl,
--C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.3-C.sub.6 cycloalkyl,
or monocyclic 5- to 7-membered heterocycloalkyl;
[0153] R.sup.7 and R.sup.8 combine to form a C.sub.3-C.sub.7
cycloalkyl, a 5- to 8-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in
C.sub.3-C.sub.7 cycloalkyl, a 5- to 8-membered heterocycloalkyl,
C.sub.6-C.sub.10 aryl, or 5- to 7-membered heteroaryl is
independently optionally substituted by deuterium, halogen, --OH,
--OC.sub.1-C.sub.6 alkyl, --OC(O)C.sub.1-C.sub.6 alkyl,
--OC(O)NH.sub.2, --OC(O)NH(C.sub.1-C.sub.6 alkyl),
--OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --OC(.dbd.N)NH.sub.2,
--OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl),
--OC(.dbd.N)N(C.sub.1-C.sub.6 alkyl).sub.2, --OS(O)C.sub.1-C.sub.6
alkyl, --OS(O).sub.2C.sub.1-C.sub.6 alkyl, --OS(O)NH.sub.2,
--OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --OS(O).sub.2NH.sub.2,
--OS(O).sub.2NH(C.sub.1-C.sub.6 alkyl),
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --SH,
--SC.sub.1-C.sub.6 alkyl, --S(O)C.sub.1-C.sub.6 alkyl,
--S(O).sub.2C.sub.1-C.sub.6 alkyl, --S(O)NH.sub.2,
--S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6
alkyl).sub.2, --S(O).sub.2NH.sub.2, --S(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --NH.sub.2,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)C.sub.1-C.sub.6 alkyl, --NHC(O)OH,
--NHC(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6 alkyl)C(O)OH,
--N(C.sub.1-C.sub.6 alkyl)C(O)OC.sub.1-C.sub.6 alkyl,
--NHC(O)NH.sub.2, --NHC(O)NH(C.sub.1-C.sub.6 alkyl),
--NHC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --NHS(O)C.sub.1-C.sub.6
alkyl, --N(C.sub.1-C.sub.6 alkyl)S(O)C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl, --NHS(O)NH.sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)S(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2NH.sub.2, --NHS(O).sub.2NH(C.sub.1-C.sub.6 alkyl),
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --C(O)OC.sub.1-C.sub.6 alkyl,
--C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --P(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)(C.sub.1-C.sub.6 alkyl).sub.2,
--P(O).sub.2(C.sub.1-C.sub.6 alkyl).sub.2, --P(O)NH.sub.2,
--P(O)NH(C.sub.1-C.sub.6 alkyl), --P(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --P(O).sub.2NH.sub.2, --P(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --P(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --P(O)OH,
--P(O)OC.sub.1-C.sub.6 alkyl, --P(O).sub.2OH,
--P(O).sub.2OC.sub.1-C.sub.6 alkyl, --CN, or --NO.sub.2;
[0154] Y is O, S, NR.sup.9, or CR.sup.9R.sup.10; and
[0155] R.sup.9 and R.sup.10 are each independently H, deuterium,
halogen, or C.sub.1-C.sub.6 alkyl, wherein each hydrogen atom in
C.sub.1-C.sub.6 alkyl is optionally substituted by a halogen, --OH,
--OC.sub.1-C.sub.6 alkyl, --OC(O)C.sub.1-C.sub.6 alkyl,
--OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --OC(O)NH(C.sub.1-C.sub.6
alkyl), --OC(O)NH.sub.2, --OC(.dbd.N)N(C.sub.1-C.sub.6
alkyl).sub.2, --OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl),
--OC(.dbd.N)NH.sub.2, --OS(O)C.sub.1-C.sub.6 alkyl,
--OS(O).sub.2C.sub.1-C.sub.6 alkyl, --OS(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O)NH.sub.2,
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --OS(O).sub.2NH.sub.2,
--SH, --SC.sub.1-C.sub.6 alkyl, --S(O)C.sub.1-C.sub.6 alkyl,
--S(O).sub.2C.sub.1-C.sub.6 alkyl, --S(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O)NH.sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --S(O).sub.2NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl).sub.2, --NH(C.sub.1-C.sub.6 alkyl),
--NH.sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)C.sub.1-C.sub.6 alkyl,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6 alkyl)C(O)OH,
--NHC(O)OC.sub.1-C.sub.6 alkyl, --NHC(O)OH, --N(C.sub.1-C.sub.6
alkyl)C(O)N(C.sub.1C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --NHC(O)N(C.sub.1C.sub.6 alkyl).sub.2,
--NHC(O)NH(C.sub.1C.sub.6 alkyl), --NHC(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O)C.sub.1-C.sub.6 alkyl,
--NHS(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O)NH.sub.2, --NHS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH.sub.2,
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2NH.sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --C(O)OC.sub.1-C.sub.6 alkyl,
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --C(O)NH(C.sub.1-C.sub.6
alkyl), --C(O)NH.sub.2, --P(C.sub.1-C.sub.6 alkyl).sub.2,
--P(O)(C.sub.1-C.sub.6 alkyl).sub.2, --P(O).sub.2(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--P(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --P(O)OC.sub.1-C.sub.6
alkyl, or --P(O).sub.2OC.sub.1-C.sub.6 alkyl.
[0156] 26. The compound of clause 25, or a pharmaceutically
acceptable salt thereof, wherein M is CR.sup.3.
[0157] 27. The compound of clause 25 or 26, or a pharmaceutically
acceptable salt thereof, wherein R.sup.3 is H, deuterium,
C.sub.1-C.sub.6 alkyl or halogen.
[0158] 28. The compound of any one of clauses 25 to 27, or a
pharmaceutically acceptable salt thereof, wherein R.sup.3 is H or
F.
[0159] 29. The compound of clause 25, or a pharmaceutically
acceptable salt thereof, wherein M is N.
[0160] 30. The compound of any one of clauses 25 to 29, or a
pharmaceutically acceptable salt thereof, wherein M.sup.1 is
CR.sup.4.
[0161] 31. The compound of any one of clauses 25 to 30, or a
pharmaceutically acceptable salt thereof, wherein R.sup.4 is H,
deuterium, C.sub.1-C.sub.6 alkyl or halogen.
[0162] 32. The compound of any one of clauses 25 to 31, or a
pharmaceutically acceptable salt thereof, wherein R.sup.4 is H or
Cl.
[0163] 33. The compound of any one of clauses 25 to 32, or a
pharmaceutically acceptable salt thereof, wherein R.sup.5 is F.
[0164] 34. The compound of any one of clauses 25 to 33, or a
pharmaceutically acceptable salt thereof, wherein R.sup.2 is H.
[0165] 35. The compound of any one of clauses 25 to 34, or a
pharmaceutically acceptable salt thereof, wherein R.sup.1 is
C.sub.1-C.sub.6 alkyl.
[0166] 36. The compound of any one of clauses 25 to 33, or a
pharmaceutically acceptable salt thereof, wherein R.sup.2 is
C.sub.1-C.sub.6 alkyl.
[0167] 36a. The compound of any one of clauses 25 to 33, or a
pharmaceutically acceptable salt thereof, wherein R.sup.2 is
C.sub.1-C.sub.6 alkyl; or C.sub.3-C.sub.7 cycloalkyl.
[0168] 37. The compound of any one of clauses 25 to 36, or a
pharmaceutically acceptable salt thereof, wherein R.sup.7 and
R.sup.8 combine to form a 5- or 6-membered cycloalkyl, wherein each
hydrogen atom in the 5- or 6-membered cycloalkyl is independently
optionally substituted by deuterium, halogen, --OH, --CN,
--OC.sub.1-C.sub.6 alkyl, --OC.sub.1-C.sub.6 alkyl(C.sub.6-C.sub.10
aryl), --NH.sub.2, --OC(O)C.sub.1-C.sub.6 alkyl,
--OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --OC(O)NH(C.sub.1-C.sub.6
alkyl), --OC(O)NH.sub.2, --OC(.dbd.N)N(C.sub.1-C.sub.6
alkyl).sub.2, --OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl),
--OC(.dbd.N)NH.sub.2, --OS(O)C.sub.1-C.sub.6 alkyl,
--OS(O).sub.2C.sub.1-C.sub.6 alkyl, --NH(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl).sub.2, --NHC(O)C.sub.1-C.sub.6 alkyl,
--N(C.sub.1-C.sub.6 alkyl)C(O)C.sub.1-C.sub.6 alkyl,
--NHC(O)NH.sub.2, --NHC(O)NH(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl)C(O)NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --NHC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --NHC(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)OC.sub.1-C.sub.6 alkyl, --NHC(O)OH, --N(C.sub.1-C.sub.6
alkyl)C(O)OH, --NHS(O)C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl, --NHS(O)NH.sub.2,
--NHS(O).sub.2NH.sub.2, --N(C.sub.1-C.sub.6 alkyl)S(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH.sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --NHS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --CO.sub.2H, --C(O)OC.sub.1-C.sub.6
alkyl, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --SC.sub.1-C.sub.6 alkyl,
--S(O)C.sub.1-C.sub.6 alkyl, --S(O).sub.2C.sub.1-C.sub.6 alkyl,
--S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --S(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --S(O)NH.sub.2,
--S(O).sub.2NH.sub.2, --OS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --OS(O)NH.sub.2, --OS(O).sub.2NH.sub.2, --P(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.3-C.sub.6
cycloalkyl, or 3- to 7-membered heterocycloalkyl.
[0169] 37a. The compound of any one of clauses 25 to 36, or a
pharmaceutically acceptable salt thereof, wherein R.sup.7 and
R.sup.8 combine to form a 4-, 5- or 6-membered cycloalkyl, wherein
each hydrogen atom in the 5- or 6-membered cycloalkyl is
independently optionally substituted by deuterium, halogen, --OH,
--CN, --OC.sub.1-C.sub.6 alkyl, --OC.sub.1-C.sub.6
alkyl(C.sub.6-C.sub.10 aryl), --NH.sub.2, --OC(O)C.sub.1-C.sub.6
alkyl, --OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(O)NH(C.sub.1-C.sub.6 alkyl), --OC(O)NH.sub.2,
--OC(.dbd.N)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl), --OC(.dbd.N)NH.sub.2,
--OS(O)C.sub.1-C.sub.6 alkyl, --OS(O).sub.2C.sub.1-C.sub.6 alkyl,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)C.sub.1-C.sub.6 alkyl, --NHC(O)NH.sub.2,
--NHC(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --NHC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --NHC(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)OC.sub.1-C.sub.6 alkyl, --NHC(O)OH, --N(C.sub.1-C.sub.6
alkyl)C(O)OH, --NHS(O)C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl, --NHS(O)NH.sub.2,
--NHS(O).sub.2NH.sub.2, --N(C.sub.1-C.sub.6 alkyl)S(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH.sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --NHS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --CO.sub.2H, --C(O)OC.sub.1-C.sub.6
alkyl, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --SC.sub.1-C.sub.6 alkyl,
--S(O)C.sub.1-C.sub.6 alkyl, --S(O).sub.2C.sub.1-C.sub.6 alkyl,
--S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --S(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --S(O)NH.sub.2,
--S(O).sub.2NH.sub.2, --OS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --OS(O)NH.sub.2, --OS(O).sub.2NH.sub.2, --P(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.3-C.sub.6
cycloalkyl, or 3- to 7-membered heterocycloalkyl.
[0170] 38. The compound of any one of clauses 25 to 36, or a
pharmaceutically acceptable salt thereof, wherein R.sup.7 and
R.sup.8 combine to form a 3-, 4-, 5- or 6-membered
heterocycloalkyl, wherein each hydrogen atom in the 3-, 4-, 5- or
6-membered heterocycloalkyl is independently optionally substituted
by deuterium, halogen, --OH, --CN, --OC.sub.1-C.sub.6 alkyl,
--OC.sub.1-C.sub.6 alkyl(C.sub.6-C.sub.10 aryl), --NH.sub.2,
--OC(O)C.sub.1-C.sub.6 alkyl, --OC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --OC(O)NH(C.sub.1-C.sub.6 alkyl), --OC(O)NH.sub.2,
--OC(.dbd.N)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl), --OC(.dbd.N)NH.sub.2,
--OS(O)C.sub.1-C.sub.6 alkyl, --OS(O).sub.2C.sub.1-C.sub.6 alkyl,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)C.sub.1-C.sub.6 alkyl, --NHC(O)NH.sub.2,
--NHC(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --NHC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --NHC(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)OC.sub.1-C.sub.6 alkyl, --NHC(O)OH, --N(C.sub.1-C.sub.6
alkyl)C(O)OH, --NHS(O)C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl, --NHS(O)NH.sub.2,
--NHS(O).sub.2NH.sub.2, --N(C.sub.1-C.sub.6 alkyl)S(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH.sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --NHS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --CO.sub.2H, --C(O)OC.sub.1-C.sub.6
alkyl, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --SC.sub.1-C.sub.6 alkyl,
--S(O)C.sub.1-C.sub.6 alkyl, --S(O).sub.2C.sub.1-C.sub.6 alkyl,
--S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --S(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --S(O)NH.sub.2,
--S(O).sub.2NH.sub.2, --OS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --OS(O)NH.sub.2, --OS(O).sub.2NH.sub.2, --P(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.3-C.sub.6
cycloalkyl, or 3- to 7-membered heterocycloalkyl.
[0171] 39. The compound of clause 38, or a pharmaceutically
acceptable salt thereof, wherein R.sup.7 and R.sup.8 combine to
form a tetrahydrofuran ring.
[0172] 40. The compound of clause 37, or a pharmaceutically
acceptable salt thereof, wherein R.sup.7 and R.sup.8 combine to
form a cyclopentane ring.
[0173] 40a. The compound of clause 37 or 37a, or a pharmaceutically
acceptable salt thereof, wherein R.sup.7 and R.sup.8 combine to
form a cyclobutane ring, cyclopentane ring, or cyclohexane
ring.
[0174] 41. The compound of any of the preceding clauses, or a
pharmaceutically acceptable salt thereof, wherein X is O.
[0175] 42. The compound of clause 1, selected from the group
consisting of
##STR00017## ##STR00018## ##STR00019##
[0176] or a pharmaceutically acceptable salt thereof.
[0177] 43. A pharmaceutical composition comprising a compound of
any one of the preceding clauses, or a pharmaceutically acceptable
salt thereof, and optionally at least one diluent, carrier or
excipient.
[0178] 44. A method of treating cancer comprising administering to
a subject in need of such treatment an effective amount of at least
one compound of any one of clauses 1 to 42, or a pharmaceutically
acceptable salt thereof.
[0179] 45. Use of a compound of any one of clauses 1 to 42, or a
pharmaceutically acceptable salt thereof, in the preparation of a
medicament for the treatment of cancer.
[0180] 46. Use of a compound of any one of clauses 1 to 42, or a
pharmaceutically acceptable salt thereof, for treating cancer.
[0181] 47. A method of inhibiting RET or SRC, comprising contacting
a cell comprising one or more of such kinases with an effective
amount of at least one compound of any one of clauses 1 to 42, or a
pharmaceutically acceptable salt thereof, and/or with at least one
pharmaceutical composition of the disclosure, wherein the
contacting is in vitro, ex vivo, or in vivo.
[0182] 48. A compound of any one of clauses 1 to 42, for use in
treating cancer in a patient.
BRIEF DESCRIPTION OF THE DRAWINGS
[0183] FIG. 1 shows the pharmacodynamic inhibiting activity of
Compound 5 on RET in RET-driven cells, specifically that Compound 5
caused the suppression of RET autophosphorylation at IC50s of
around 0.3 nM in TT.
[0184] FIG. 2 shows the pharmacodynamic inhibiting activity of
Compound 5 on RET in RET-driven cells, specifically that Compound 5
caused the suppression of RET autophosphorylation at IC50s of
around 1-3 nM in Ba/F3 KIF5B-RET WT.
[0185] FIG. 3 shows the pharmacodynamic inhibiting activity of
Compound 5 on RET in RET-driven cells, specifically that Compound 5
caused the suppression of RET autophosphorylation at IC50s of
around 3-10 nM in Ba/F3 KIF5B-RET G810R.
[0186] FIG. 4A is a chart that shows that Compound 5 dosed at 2
mg/kg BID and 5 mg/kg BID for 27 days decreased tumor size in test
mice compared to untreated control. Untreated control (), 2 mg/kg
(), 5 mg/kg ().
[0187] FIG. 4B is a chart that shows % weight change for test mice
dosed at 2 mg/kg BID and 5 mg/kg BID for 27 days compared to
untreated control. Untreated control (), 2 mg/kg (), 5 mg/kg
().
[0188] FIG. 5A is a chart that shows the effect of Compound 5 dosed
at 1 mg/kg BID and 5 mg/kg BID for 10 days on tumor size in test
mice compared to untreated control. Untreated control (), 1 mg/kg
(), 5 mg/kg ().
[0189] FIG. 5B is a chart that shows % weight change for test mice
dosed at 1 mg/kg BID and 5 mg/kg BID for 10 days compared to
untreated control. Untreated control (), 1 mg/kg (), 5 mg/kg
().
[0190] FIG. 6A is a chart that shows the effect of Compound 5 dosed
at 1 mg/kg BID, 5 mg/kg BID, and 10 mg/kg BID for 14 days on tumor
size in test mice compared to untreated control. Untreated control
(), 1 mg/kg (), 5 mg/kg (), 10 mg/kg ().
[0191] FIG. 6B is a chart that shows % weight change for test mice
dosed at 1 mg/kg BID, 5 mg/kg BID, and 10 mg/kg BID for 14 days
compared to untreated control. Untreated control (), 1 mg/kg (), 5
mg/kg (), 10 mg/kg ().
[0192] FIG. 7A is a chart that shows the effect of Compound 5 dosed
at 1 mg/kg BID and 5 mg/kg BID for 21 days on tumor size in test
mice compared to untreated control. Untreated control (), 1 mg/kg
(), 5 mg/kg ().
[0193] FIG. 7B is a chart that shows % weight change for test mice
dosed at 1 mg/kg BID and 5 mg/kg BID for 21 days compared to
untreated control. Untreated control (), 1 mg/kg (), 5 mg/kg
().
[0194] FIG. 8A is a chart that shows the effect of Compound 5 dosed
at 1 mg/kg, 2 mg/kg, or 5 mg/kg BID for 10 days on tumor size in
test mice compared to untreated control. Untreated control (), 1
mg/kg (), 2 mg/kg (), 5 mg/kg (). FIG. 8B is a chart that shows the
effect of Compound 5 dosed at 1 mg/kg, 2 mg/kg, or 5 mg/kg BID for
10 days on body weight in test mice compared to untreated control.
Untreated control (), 1 mg/kg (), 2 mg/kg (), 5 mg/kg ().
DETAILED DESCRIPTION
[0195] Before the present disclosure is further described, it is to
be understood that this disclosure is not limited to particular
embodiments described, as such may, of course, vary. It is also to
be understood that the terminology used herein is for the purpose
of describing particular embodiments only, and is not intended to
be limiting, since the scope of the present disclosure will be
limited only by the appended claims.
[0196] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of ordinary skill in the art to which this disclosure belongs. All
patents, applications, published applications and other
publications referred to herein are incorporated by reference in
their entireties. If a definition set forth in this section is
contrary to or otherwise inconsistent with a definition set forth
in a patent, application, or other publication that is herein
incorporated by reference, the definition set forth in this section
prevails over the definition incorporated herein by reference.
[0197] As used herein and in the appended claims, the singular
forms "a," "an," and "the" include plural referents unless the
context clearly dictates otherwise. It is further noted that the
claims may be drafted to exclude any optional element. As such,
this statement is intended to serve as antecedent basis for use of
such exclusive terminology as "solely," "only" and the like in
connection with the recitation of claim elements, or use of a
"negative" limitation.
[0198] As used herein, the terms "including," "containing," and
"comprising" are used in their open, non-limiting sense.
[0199] To provide a more concise description, some of the
quantitative expressions given herein are not qualified with the
term "about". It is understood that, whether the term "about" is
used explicitly or not, every quantity given herein is meant to
refer to the actual given value, and it is also meant to refer to
the approximation to such given value that would reasonably be
inferred based on the ordinary skill in the art, including
equivalents and approximations due to the experimental and/or
measurement conditions for such given value. Whenever a yield is
given as a percentage, such yield refers to a mass of the entity
for which the yield is given with respect to the maximum amount of
the same entity that could be obtained under the particular
stoichiometric conditions. Concentrations that are given as
percentages refer to mass ratios, unless indicated differently.
[0200] Except as otherwise noted, the methods and techniques of the
present embodiments are generally performed according to
conventional methods well known in the art and as described in
various general and more specific references that are cited and
discussed throughout the present specification. See, e.g., Loudon,
Organic Chemistry, Fourth Edition, New York: Oxford University
Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's
Advanced Organic Chemistry: Reactions, Mechanisms, and Structure,
Fifth Edition, Wiley-Interscience, 2001.
[0201] Chemical nomenclature for compounds described herein has
generally been derived using the commercially-available ACD/Name
2014 (ACD/Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer).
[0202] It is appreciated that certain features of the disclosure,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the disclosure, which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable subcombination.
All combinations of the embodiments pertaining to the chemical
groups represented by the variables are specifically embraced by
the present disclosure and are disclosed herein just as if each and
every combination was individually and explicitly disclosed, to the
extent that such combinations embrace compounds that are stable
compounds (i.e., compounds that can be isolated, characterized, and
tested for biological activity). In addition, all subcombinations
of the chemical groups listed in the embodiments describing such
variables are also specifically embraced by the present disclosure
and are disclosed herein just as if each and every such
sub-combination of chemical groups was individually and explicitly
disclosed herein.
Definitions
[0203] As used herein, the term "alkyl" includes a chain of carbon
atoms, which is optionally branched and contains from 1 to 20
carbon atoms. It is to be further understood that in certain
embodiments, alkyl may be advantageously of limited length,
including C.sub.1-C.sub.12, C.sub.1-C.sub.10, C.sub.1-C.sub.9,
C.sub.1-C.sub.8, C.sub.1-C.sub.7, C.sub.1-C.sub.6, and
C.sub.1-C.sub.4, Illustratively, such particularly limited length
alkyl groups, including C.sub.1-C.sub.8, C.sub.1-C.sub.7,
C.sub.1-C.sub.6, and C.sub.1-C.sub.4, and the like may be referred
to as "lower alkyl." Illustrative alkyl groups include, but are not
limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl,
hexyl, heptyl, octyl, and the like. Alkyl may be substituted or
unsubstituted. Typical substituent groups include cycloalkyl, aryl,
heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto,
alkylthio, arylthio, cyano, halo, carbonyl, oxo, (.dbd.O),
thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro, and
amino, or as described in the various embodiments provided herein.
It will be understood that "alkyl" may be combined with other
groups, such as those provided above, to form a functionalized
alkyl. By way of example, the combination of an "alkyl" group, as
described herein, with a "carboxy" group may be referred to as a
"carboxyalkyl" group. Other non-limiting examples include
hydroxyalkyl, aminoalkyl, and the like.
[0204] As used herein, the term "alkenyl" includes a chain of
carbon atoms, which is optionally branched, and contains from 2 to
20 carbon atoms, and also includes at least one carbon-carbon
double bond (i.e. C.dbd.C). It will be understood that in certain
embodiments, alkenyl may be advantageously of limited length,
including C.sub.2-C.sub.12, C.sub.2-C.sub.9, C.sub.2-C.sub.8,
C.sub.2-C.sub.7, C.sub.2-C.sub.6, and C.sub.2-C.sub.4.
Illustratively, such particularly limited length alkenyl groups,
including C.sub.2-C.sub.8, C.sub.2-C.sub.7, C.sub.2-C.sub.6, and
C.sub.2-C.sub.4 may be referred to as lower alkenyl. Alkenyl may be
unsubstituted, or substituted as described for alkyl or as
described in the various embodiments provided herein. Illustrative
alkenyl groups include, but are not limited to, ethenyl,
1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.
[0205] As used herein, the term "alkynyl" includes a chain of
carbon atoms, which is optionally branched, and contains from 2 to
20 carbon atoms, and also includes at least one carbon-carbon
triple bond (i.e. C.ident.C). It will be understood that in certain
embodiments, alkynyl may each be advantageously of limited length,
including C.sub.2-C.sub.12, C.sub.2-C.sub.9, C.sub.2-C.sub.8,
C.sub.2-C.sub.7, C.sub.2-C.sub.6, and C.sub.2-C.sub.4.
Illustratively, such particularly limited length alkynyl groups,
including C.sub.2-C.sub.8, C.sub.2-C.sub.7, C.sub.2-C.sub.6, and
C.sub.2-C.sub.4 may be referred to as lower alkynyl. Alkenyl may be
unsubstituted, or substituted as described for alkyl or as
described in the various embodiments provided herein. Illustrative
alkenyl groups include, but are not limited to, ethynyl,
1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
[0206] As used herein, the term "aryl" refers to an all-carbon
monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms
having a completely conjugated pi-electron system. It will be
understood that in certain embodiments, aryl may be advantageously
of limited size such as C.sub.6-C.sub.10 aryl. Illustrative aryl
groups include, but are not limited to, phenyl, naphthylenyl and
anthracenyl. The aryl group may be unsubstituted, or substituted as
described for alkyl or as described in the various embodiments
provided herein.
[0207] As used herein, the term "cycloalkyl" refers to a 3 to 15
member all-carbon monocyclic ring, including an all-carbon
5-member/6-member or 6-member/6-member fused bicyclic ring, or a
multicyclic fused ring (a "fused" ring system means that each ring
in the system shares an adjacent pair of carbon atoms with each
other ring in the system) group, or a carbocyclic ring that is
fused to another group such as a heterocyclic, such as ring 5- or
6-membered cycloalkyl fused to a 5- to 7-membered heterocyclic
ring, where one or more of the rings may contain one or more double
bonds but the cycloalkyl does not contain a completely conjugated
pi-electron system. It will be understood that in certain
embodiments, cycloalkyl may be advantageously of limited size such
as C.sub.3-C.sub.13, C.sub.3-C.sub.9, C.sub.3-C.sub.6 and
C.sub.4-C.sub.6. Cycloalkyl may be unsubstituted, or substituted as
described for alkyl or as described in the various embodiments
provided herein. Illustrative cycloalkyl groups include, but are
not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,
cycloheptyl, adamantyl, norbornyl, norbornenyl, 9H-fluoren-9-yl,
and the like. Illustrative examples of cycloalkyl groups shown in
graphical representations include the following entities, in the
form of properly bonded moieties:
##STR00020##
[0208] As used herein, the term "heterocycloalkyl" refers to a
monocyclic or fused ring group having in the ring(s) from 3 to 12
ring atoms, in which at least one ring atom is a heteroatom, such
as nitrogen, oxygen or sulfur, the remaining ring atoms being
carbon atoms. Heterocycloalkyl may optionally contain 1, 2, 3 or 4
heteroatoms. A heterocycloalkyl group may be fused to another group
such as another heterocycloalkyl, or a heteroaryl group.
Heterocycloalkyl may also have one or more double bonds, including
double bonds to nitrogen (e.g. C.dbd.N or N.dbd.N) but does not
contain a completely conjugated pi-electron system. It will be
understood that in certain embodiments, heterocycloalkyl may be
advantageously of limited size such as 3- to 7-membered
heterocycloalkyl, 5- to 7-membered heterocycloalkyl, 3-, 4-, 5- or
6-membered heterocycloalkyl, and the like. Heterocycloalkyl may be
unsubstituted, or substituted as described for alkyl or as
described in the various embodiments provided herein. Illustrative
heterocycloalkyl groups include, but are not limited to, oxiranyl,
thianaryl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl,
1,4-dithianyl, piperazinyl, oxepanyl, 3,4-dihydro-2H-pyranyl,
5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1, 2, 3, 4-tetrahydropyridinyl,
and the like. Illustrative examples of heterocycloalkyl groups
shown in graphical representations include the following entities,
in the form of properly bonded moieties:
##STR00021##
[0209] As used herein, the term "heteroaryl" refers to a monocyclic
or fused ring group of 5 to 12 ring atoms containing one, two,
three or four ring heteroatoms selected from nitrogen, oxygen and
sulfur, the remaining ring atoms being carbon atoms, and also
having a completely conjugated pi-electron system. It will be
understood that in certain embodiments, heteroaryl may be
advantageously of limited size such as 3- to 7-membered heteroaryl,
5- to 7-membered heteroaryl, and the like. Heteroaryl may be
unsubstituted, or substituted as described for alkyl or as
described in the various embodiments provided herein. Illustrative
heteroaryl groups include, but are not limited to, pyrrolyl,
furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl,
pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl,
tetrazolyl, triazinyl, pyrazinyl, tetrazinyl, quinazolinyl,
quinoxalinyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl,
thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl,
benzthiazolyl, benzisoxazolyl, benzisothiazolyl and carbazoloyl,
and the like. Illustrative examples of heteroaryl groups shown in
graphical representations, include the following entities, in the
form of properly bonded moieties:
##STR00022##
[0210] As used herein, "hydroxy" or ""hydroxyl" refers to an --OH
group.
[0211] As used herein, "alkoxy" refers to both an --O-(alkyl) or an
--O-(unsubstituted cycloalkyl) group. Representative examples
include, but are not limited to, methoxy, ethoxy, propoxy, butoxy,
cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and
the like.
[0212] As used herein, "aryloxy" refers to an --O-aryl or an
--O-heteroaryl group. Representative examples include, but are not
limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy,
pyrimidinyloxy, pyrazinyloxy, and the like, and the like.
[0213] As used herein, "mercapto" refers to an --SH group.
[0214] As used herein, "alkylthio" refers to an --S-(alkyl) or an
--S-(unsubstituted cycloalkyl) group. Representative examples
include, but are not limited to, methylthio, ethylthio, propylthio,
butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio,
cyclohexylthio, and the like.
[0215] As used herein, "arylthio" refers to an --S-aryl or an
--S-heteroaryl group. Representative examples include, but are not
limited to, phenylthio, pyridinylthio, furanylthio, thienylthio,
pyrimidinylthio, and the like.
[0216] As used herein, "halo" or "halogen" refers to fluorine,
chlorine, bromine or iodine.
[0217] As used herein, "cyano" refers to a --CN group.
[0218] The term "oxo" represents a carbonyl oxygen. For example, a
cyclopentyl substituted with oxo is cyclopentanone.
[0219] As used herein, "bond" refers to a covalent bond.
[0220] The term "substituted" means that the specified group or
moiety bears one or more substituents. The term "unsubstituted"
means that the specified group bears no substituents. Where the
term "substituted" is used to describe a structural system, the
substitution is meant to occur at any valency-allowed position on
the system. In some embodiments, "substituted" means that the
specified group or moiety bears one, two, or three substituents. In
other embodiments, "substituted" means that the specified group or
moiety bears one or two substituents. In still other embodiments,
"substituted" means the specified group or moiety bears one
substituent.
[0221] As used herein, "optional" or "optionally" means that the
subsequently described event or circumstance may but need not
occur, and that the description includes instances where the event
or circumstance occurs and instances in which it does not. For
example, "wherein each hydrogen atom in C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or mono- or bicyclic heteroaryl is independently optionally
substituted by C.sub.1-C.sub.6 alkyl" means that an alkyl may be
but need not be present on any of the C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or mono- or bicyclic heteroaryl by replacement of a hydrogen
atom for each alkyl group, and the description includes situations
where the C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, or mono- or
bicyclic heteroaryl is substituted with an alkyl group and
situations where the C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, or mono- or
bicyclic heteroaryl is not substituted with the alkyl group.
[0222] As used herein, "independently" means that the subsequently
described event or circumstance is to be read on its own relative
to other similar events or circumstances. For example, in a
circumstance where several equivalent hydrogen groups are
optionally substituted by another group described in the
circumstance, the use of "independently optionally" means that each
instance of a hydrogen atom on the group may be substituted by
another group, where the groups replacing each of the hydrogen
atoms may be the same or different. Or for example, where multiple
groups exist all of which can be selected from a set of
possibilities, the use of "independently" means that each of the
groups can be selected from the set of possibilities separate from
any other group, and the groups selected in the circumstance may be
the same or different.
[0223] As used herein, the phrase "taken together with the carbon
to which they are attached" or "taken together with the carbon atom
to which they are attached" means that two substituents (e.g.
R.sup.1 and R.sup.2) attached to the same carbon atom form the
groups that are defined by the claim, such as C.sub.3-C.sub.6
cycloalkyl or a 4- to 6-membered heterocycloalkyl. In particular,
the phrase "taken together with the carbon to which they are
attached" means that when, for example, R.sup.1 and R.sup.2, and
the carbon atom to which they are attached form a C.sub.3-C.sub.6
cycloalkyl, then the formed ring will be attached at the same
carbon atom. For example, the phrase "R.sup.1 and R.sup.2 taken
together with the carbon to which they are attached form a
C.sub.3-C.sub.6 cycloalkyl" used in connection with the embodiments
described herein includes fragments represented as follows:
##STR00023##
[0224] where the above spirocyclic rings can be optionally
substituted as defined in a given embodiment.
[0225] As used herein, the phrase "taken together with the carbons
to which they are attached" or "taken together with the carbon
atoms to which they are attached" means that two substituents (e.g.
R.sup.1 and R.sup.2) attached to different carbon atoms form the
groups that are defined by the claim, such as C.sub.3-C.sub.6
cycloalkyl or a 4- to 6-membered heterocycloalkyl. In particular,
the phrase "taken together with the carbons to which they are
attached form a" means that when, for example, R.sup.1 and R.sup.2,
and the carbon atoms, which are not the same carbon atom, to which
they are attached form a C.sub.3-C.sub.6 cycloalkyl, then the
formed ring will be attached at different carbon atoms. For
example, the phrase "R.sup.1 and R.sup.2 taken together with the
carbons to which they are attached form a C.sub.3-C.sub.6
cycloalkyl" used in connection with the embodiments described
herein includes fragments represented as follows:
##STR00024##
[0226] where the above fused rings can be optionally substituted as
defined in a given embodiment. Likewise, the phrase "R.sup.7 and
R.sup.8 combine to form a C.sub.3-C.sub.7 cycloalkyl, a 5- to
8-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, or 5- to
7-membered heteroaryl" also means that R.sup.7 and R.sup.8 are
taken together with the carbon atoms to which they are attached to
form a C.sub.3-C.sub.7 cycloalkyl, a 5- to 8-membered
heterocycloalkyl, C.sub.6-C.sub.10 aryl, or 5- to 7-membered
heteroaryl. In particular, "R.sup.7 and R.sup.8 combine to form a
C.sub.3-C.sub.7 cycloalkyl" used in connection with the embodiments
described herein includes fragments represented by the
following:
##STR00025##
[0227] where the above fused rings can be optionally substituted as
defined in a given embodiment. One of skill in the art will
appreciate that all stereochemical arrangements are included within
the structures provided above, such as with respect to the
five-carbon ring formed by R.sup.7 and R.sup.8 as provided in the
following fragments:
##STR00026##
[0228] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which counter ions which may be used in
pharmaceuticals. See, generally, S. M. Berge, et al.,
"Pharmaceutical Salts," J. Pharm. Sci., 1977, 66, 1-19. Preferred
pharmaceutically acceptable salts are those that are
pharmacologically effective and suitable for contact with the
tissues of subjects without undue toxicity, irritation, or allergic
response. A compound described herein may possess a sufficiently
acidic group, a sufficiently basic group, both types of functional
groups, or more than one of each type, and accordingly react with a
number of inorganic or organic bases, and inorganic and organic
acids, to form a pharmaceutically acceptable salt. Such salts
include:
[0229] (1) acid addition salts, which can be obtained by reaction
of the free base of the parent compound with inorganic acids such
as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric
acid, sulfuric acid, and perchloric acid and the like, or with
organic acids such as acetic acid, oxalic acid, (D) or (L) malic
acid, maleic acid, methane sulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid,
succinic acid or malonic acid and the like; or
[0230] (2) salts formed when an acidic proton present in the parent
compound either is replaced by a metal ion, e.g., an alkali metal
ion, an alkaline earth ion, or an aluminum ion; or coordinates with
an organic base such as ethanolamine, diethanolamine,
triethanolamine, trimethamine, N-methylglucamine, and the like.
[0231] Pharmaceutically acceptable salts are well known to those
skilled in the art, and any such pharmaceutically acceptable salt
may be contemplated in connection with the embodiments described
herein. Examples of pharmaceutically acceptable salts include
sulfates, pyrosulfates, bisulfates, sulfites, bisulfites,
phosphates, monohydrogen-phosphates, dihydrogenphosphates,
metaphosphates, pyrophosphates, chlorides, bromides, iodides,
acetates, propionates, decanoates, caprylates, acrylates, formates,
isobutyrates, caproates, heptanoates, propiolates, oxalates,
malonates, succinates, suberates, sebacates, fumarates, maleates,
butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates,
methylbenzoates, dinitrobenzoates, hydroxybenzoates,
methoxybenzoates, phthalates, sulfonates, methylsulfonates,
propylsulfonates, besylates, xylenesulfonates,
naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates,
phenylpropionates, phenylbutyrates, citrates, lactates,
.gamma.-hydroxybutyrates, glycolates, tartrates, and mandelates.
Lists of other suitable pharmaceutically acceptable salts are found
in Remington's Pharmaceutical Sciences, 17th Edition, Mack
Publishing Company, Easton, Pa., 1985.
[0232] For a compound of Formula I, II, III, IV or V that contains
a basic nitrogen, a pharmaceutically acceptable salt may be
prepared by any suitable method available in the art, for example,
treatment of the free base with an inorganic acid, such as
hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid,
nitric acid, boric acid, phosphoric acid, and the like, or with an
organic acid, such as acetic acid, phenylacetic acid, propionic
acid, stearic acid, lactic acid, ascorbic acid, maleic acid,
hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,
fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic
acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a
pyranosidyl acid, such as glucuronic acid or galacturonic acid, an
alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric
acid, an amino acid, such as aspartic acid or glutamic acid, an
aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid,
naphthoic acid, or cinnamic acid, a sulfonic acid, such as
laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid,
or ethanesulfonic acid, or any compatible mixture of acids such as
those given as examples herein, and any other acid and mixture
thereof that are regarded as equivalents or acceptable substitutes
in light of the ordinary level of skill in this technology.
[0233] The disclosure also relates to pharmaceutically acceptable
prodrugs of the compounds of Formula I, II, III, IV or V, and
treatment methods employing such pharmaceutically acceptable
prodrugs. The term "prodrug" means a precursor of a designated
compound that, following administration to a subject, yields the
compound in vivo via a chemical or physiological process such as
solvolysis or enzymatic cleavage, or under physiological conditions
(e.g., a prodrug on being brought to physiological pH is converted
to the compound of Formula I, II, III, IV or V). A
"pharmaceutically acceptable prodrug" is a prodrug that is
non-toxic, biologically tolerable, and otherwise biologically
suitable for administration to the subject. Illustrative procedures
for the selection and preparation of suitable prodrug derivatives
are described, for example, in "Design of Prodrugs", ed. H.
Bundgaard, Elsevier, 1985.
[0234] The present disclosure also relates to pharmaceutically
active metabolites of compounds of Formula I, II, III, IV or V, and
uses of such metabolites in the methods of the disclosure. A
"pharmaceutically active metabolite" means a pharmacologically
active product of metabolism in the body of a compound of Formula
I, II, III, IV or V, or salt thereof. Prodrugs and active
metabolites of a compound may be determined using routine
techniques known or available in the art. See, e.g., Bertolini et
al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci.
1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230;
Bodor, Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design of
Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application
of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al.,
eds., Harwood Academic Publishers, 1991).
[0235] Any formula depicted herein is intended to represent a
compound of that structural formula as well as certain variations
or forms. For example, a formula given herein is intended to
include a racemic form, or one or more enantiomeric,
diastereomeric, or geometric isomers, or a mixture thereof.
Additionally, any formula given herein is intended to refer also to
a hydrate, solvate, or polymorph of such a compound, or a mixture
thereof. For example, it will be appreciated that compounds
depicted by a structural formula containing the symbol "" include
both stereoisomers for the carbon atom to which the symbol "" is
attached, specifically both the bonds "" and "" are encompassed by
the meaning of "". For example, in some exemplary embodiments,
certain compounds provided herein can be described by the
formula
##STR00027##
[0236] which formula will be understood to encompass compounds
having both stereochemical configurations at the relevant carbon
atom, specifically in this example
##STR00028## ##STR00029##
and other stereochemical combinations.
[0237] Any formula given herein is also intended to represent
unlabeled forms as well as isotopically labeled forms of the
compounds. Isotopically labeled compounds have structures depicted
by the formulas given herein except that one or more atoms are
replaced by an atom having a selected atomic mass or mass number.
Examples of isotopes that can be incorporated into compounds of the
disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorous, fluorine, chlorine, and iodine, such as .sup.2H,
.sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.15N, .sup.18O,
.sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, .sup.36Cl, and
.sup.125I, respectively. Such isotopically labelled compounds are
useful in metabolic studies (preferably with .sup.14C), reaction
kinetic studies (with, for example .sup.2H or .sup.3H), detection
or imaging techniques [such as positron emission tomography (PET)
or single-photon emission computed tomography (SPECT)] including
drug or substrate tissue distribution assays, or in radioactive
treatment of patients. Further, substitution with heavier isotopes
such as deuterium (i.e., .sup.2H) may afford certain therapeutic
advantages resulting from greater metabolic stability, for example
increased in vivo half-life or reduced dosage requirements.
Isotopically labeled compounds of this disclosure and prodrugs
thereof can generally be prepared by carrying out the procedures
disclosed in the schemes or in the examples and preparations
described below by substituting a readily available isotopically
labeled reagent for a non-isotopically labeled reagent.
[0238] Any disubstituent referred to herein is meant to encompass
the various attachment possibilities when more than one of such
possibilities are allowed. For example, reference to disubstituent
-A-B--, where A.noteq.B, refers herein to such disubstituent with A
attached to a first substituted member and B attached to a second
substituted member, and it also refers to such disubstituent with A
attached to the second substituted member and B attached to the
first substituted member.
REPRESENTATIVE EMBODIMENTS
[0239] In some embodiments, compounds described herein comprise a
moiety of the formula
##STR00030##
wherein Z.sup.1-Z.sup.6 and Y are defined as described herein, and
the substituents on the non-aromatic ring marked by a bond and
.about. correspond to R.sup.7 and R.sup.8 as described herein. In
other embodiments, compounds described herein comprise a moiety of
the formula
##STR00031##
wherein Z.sup.1-Z.sup.6, R.sup.9, and R.sup.10 are otherwise
defined as described herein, and the substituents on the
non-aromatic ring marked by a bond and .about. correspond to
R.sup.7 and R.sup.8 as described herein. In still other
embodiments, compounds described herein comprise a moiety of the
formula
##STR00032##
[0240] wherein Z.sup.1-Z.sup.6 and Y are otherwise defined as
described herein, and the substituents on the non-aromatic ring
marked by a bond and .about. correspond to R.sup.7 and R.sup.8 as
described herein. In some embodiments, each of Z.sup.1, Z.sup.2,
Z.sup.3, Z.sup.4, Z.sup.5, and Z.sup.6 is independently N, NH, C or
CH. In some embodiments, Z.sup.1, Z.sup.3 and Z.sup.6 are N,
Z.sup.2 and Z.sup.5 are CH, and Z.sup.4 is C. In some embodiments,
Z.sup.1, Z.sup.3 and Z.sup.6 are N, Z.sup.2 and Z.sup.5 are CH,
Z.sup.4 is C, and Y is O. In some embodiments, Z.sup.1, Z.sup.2 and
Z.sup.6 are N, Z.sup.5 is CH, and Z.sup.3 and Z.sup.4 are C. In
some embodiments, Z.sup.1, Z.sup.2 and Z.sup.6 are N, Z.sup.5 is
CH, Z.sup.3 and Z.sup.4 are C, and Y is O. In some embodiments,
Z.sup.2, Z and Z.sup.5 are N, Z and Z.sup.6 are CH, and Z.sup.3 is
C. In some embodiments, Z.sup.2, Z.sup.4 and Z.sup.5 are N, Z.sup.1
and Z.sup.6 are CH, Z.sup.3 is C and Y is O. In some embodiments,
Z.sup.1, Z.sup.4 and Z.sup.6 are N, Z.sup.2 and Z.sup.5 are CH, and
Z.sup.3 is C. In some embodiments, Z.sup.1, Z.sup.4 and Z.sup.6 are
N, Z.sup.2 and Z.sup.5 are CH, Z.sup.3 is C, and Y is O. In some
embodiments, Z.sup.2 and Z.sup.4 are N, Z.sup.6, Z.sup.5 and
Z.sup.6 are CH, and Z.sup.3 is C. In some embodiments, Z.sup.2 and
Z.sup.4 are N, Z.sup.1, Z.sup.5 and Z.sup.6 are CH, Z.sup.3 is C,
and Y is O.
[0241] In still other embodiments, compounds described herein
comprise a moiety of the formula
##STR00033##
wherein Y is otherwise defined as described herein, and the
substituents on the non-aromatic ring marked by a bond and .about.
correspond to R.sup.7 and R.sup.8 as described herein. In still
other embodiments, compounds described herein comprise a moiety of
the formula
##STR00034##
wherein Y is otherwise defined as described herein. In still other
embodiments, compounds described herein comprise a moiety of the
formula
##STR00035##
In still other embodiments, compounds described herein comprise a
moiety of the formula
##STR00036##
In still other embodiments, compounds described herein comprise a
moiety of the formula
##STR00037##
In still other embodiments, compounds described herein comprise a
moiety of the formula
##STR00038##
[0242] In some embodiments, L is --C(R.sup.1)(R.sup.2)--. In some
embodiments, L is X. In some embodiments, when t is 1, L is
--C(R.sup.1)(R.sup.2)--.
[0243] In some embodiments, X is --O--. In some embodiments, X is
--S--. In some embodiments, X is --S(O)--. In some embodiments, X
is --S(O).sub.2. In some embodiments, when t is 1, L is not X. In
some embodiments, when t is 2, 2, or 4, the L attached directly to
the amide nitrogen in the macrocycle is not X.
[0244] In some embodiments, each R.sup.1 and R.sup.2 is
independently H, deuterium, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or mono- or bicyclic heteroaryl, --OR.sup.a, --OC(O)R.sup.a,
--OC(O)R.sup.a, --OC(O)NR.sup.aR.sup.b, --OS(O)R.sup.a,
--OS(O).sub.2R.sup.a, --SR.sup.a, --S(O)R.sup.a,
--S(O).sub.2R.sup.a, --S(O)NR.sup.aR.sup.b,
--S(O).sub.2NR.sup.aR.sup.b, --OS(O)NR.sup.aR.sup.b,
--OS(O).sub.2NR.sup.aR.sup.b, --NR.sup.aR.sup.b,
--NR.sup.aC(O)R.sup.b, --NR.sup.aC(O)OR.sup.b,
--NR.sup.aC(O)NR.sup.aR.sup.b, --NR.sup.aS(O)R.sup.b,
--NR.sup.aS(O).sub.2R.sup.b, --NR.sup.aS(O)NR.sup.aR.sup.b,
--NR.sup.aS(O).sub.2NR.sup.aR.sup.b, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.aR.sup.b, --PR.sup.aR.sup.b, --P(O)R.sup.aR.sup.b,
--P(O).sub.2R.sup.aR.sup.b, --P(O)NR.sup.aR.sup.b,
--P(O).sub.2NR.sup.aR.sup.b, --P(O)OR.sup.a, --P(O).sub.2OR.sup.a,
--CN, or --NO.sub.2, or R.sup.1 and R.sup.2 taken together with the
carbon or carbons to which they are attached form a C.sub.3-C.sub.6
cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each
hydrogen atom in C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to
7-membered heterocycloalkyl, C.sub.6-C.sub.10 aryl, mono- or
bicyclic heteroaryl, 4- to 6-membered heterocycloalkyl is
independently optionally substituted by deuterium, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, --OR.sup.e,
--OC(O)R.sup.e, --OC(O)NR.sup.eR.sup.f,
--OC(.dbd.N)NR.sup.eR.sup.f, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e,
--OS(O)NR.sup.eR.sup.f, --OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e,
--S(O)R.sup.e, --S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.t,
--NR.sup.eS(O).sub.2R.sup.t, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2.
[0245] In some embodiments, R.sup.1 and R.sup.2 are each
independently H, deuterium, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.6-C.sub.10 aryl, --OR.sup.a, --SR.sup.a, --NR.sup.aR.sup.b,
--C(O)OR.sup.a, --C(O)NR.sup.aR.sup.b; wherein each hydrogen atom
in C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl and C.sub.6-C.sub.10 aryl is
independently optionally substituted by deuterium, halogen, --OH,
--CN, --OC.sub.1-C.sub.6 alkyl, --OC.sub.1-C.sub.6
alkyl(C.sub.6-C.sub.10 aryl), --NH.sub.2, --OC(O)C.sub.1-C.sub.6
alkyl, --OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(O)NH(C.sub.1-C.sub.6 alkyl), --OC(O)NH.sub.2,
--OC(.dbd.N)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl), --OC(.dbd.N)NH.sub.2,
--OS(O)C.sub.1-C.sub.6 alkyl, --OS(O).sub.2C.sub.1-C.sub.6 alkyl,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)C.sub.1-C.sub.6 alkyl, --NHC(O)NH.sub.2,
--NHC(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --NHC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --NHC(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)OC.sub.1-C.sub.6 alkyl, --NHC(O)OH, --N(C.sub.1-C.sub.6
alkyl)C(O)OH, --NHS(O)C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl, --NHS(O)NH.sub.2,
--NHS(O).sub.2NH.sub.2, --N(C.sub.1-C.sub.6 alkyl)S(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH.sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --NHS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --CO.sub.2H, --C(O)OC.sub.1-C.sub.6
alkyl, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --SC.sub.1-C.sub.6 alkyl,
--S(O)C.sub.1-C.sub.6 alkyl, --S(O).sub.2C.sub.1-C.sub.6 alkyl,
--S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --S(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --S(O)NH.sub.2,
--S(O).sub.2NH.sub.2, --OS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --OS(O)NH.sub.2, --OS(O).sub.2NH.sub.2, --P(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.3-C.sub.6
cycloalkyl, or 3- to 7-membered heterocycloalkyl.
[0246] In some embodiments, R.sup.1 is H. In some embodiments,
R.sup.2 is H. In some embodiments, R.sup.1 is C.sub.1-C.sub.6
alkyl. In some embodiments, R.sup.1 is methyl. In some embodiments,
R.sup.1 is C.sub.3-C.sub.6 cycloalkyl. In some embodiments, R.sup.1
is cyclopropyl. In some embodiments, R.sup.2 is C.sub.1-C.sub.6
alkyl. In some embodiments, R.sup.2 is methyl. In some embodiments,
R.sup.2 is C.sub.3-C.sub.6 cycloalkyl. In some embodiments, R.sup.2
is cyclopropyl. In some embodiments, R.sup.1 is H and R.sup.2 is
C.sub.1-C.sub.6 alkyl. In some embodiments, R.sup.1 and R.sup.2
taken together with the carbon or carbons to which they are
attached form a C.sub.3-C.sub.6 cycloalkyl. In some embodiments,
R.sup.1 and R.sup.2 taken together with the carbon or carbons to
which they are attached form a cyclopropane ring.
[0247] In some embodiments, M is CR.sup.3. In some embodiments, M
is N. In some embodiments, M.sup.1 is CR.sup.4.
[0248] In some embodiments, each R.sup.3, R.sup.4, and R.sup.5 is
independently hydrogen, deuterium, halogen, --OR.sup.c,
--OC(O)R.sup.c, --OC(O)NR.sup.eR.sup.d,
--OC(.dbd.N)NR.sup.eR.sup.d, --OS(O)R.sup.c, --OS(O).sub.2R.sup.c,
--OS(O)NR.sup.eR.sup.d, --OS(O).sub.2NR.sup.eR.sup.d, --SR.sup.c,
--S(O)R.sup.c, --S(O).sub.2R.sup.c, --S(O)NR.sup.eR.sup.d,
--S(O).sub.2NR.sup.eR.sup.d, --NR.sup.eR.sup.d,
--NR.sup.cC(O)R.sup.d, --NR.sup.c'C(O)OR.sup.d,
--NR.sup.cC(O)NR.sup.cR.sup.d, --NR.sup.cC(.dbd.N)NR.sup.cR.sup.d,
--NR.sup.cS(O)R.sup.d, --NR.sup.cS(O).sub.2R.sup.d,
--NR.sup.cS(O)NR.sup.cR.sup.d, --NR.sup.cS(O).sub.2NR.sup.cR.sup.d,
--C(O)R.sup.c, --C(O)OR.sup.c, --C(O)NR.sup.cR.sup.d,
--C(.dbd.N)NR.sup.cR.sup.d, --PR.sup.cR.sup.d,
--P(O)R.sup.cR.sup.d, --P(O).sub.2R.sup.cR.sup.d,
--P(O)NR.sup.cR.sup.d, --P(O).sub.2NR.sup.cR.sup.d, --P(O)OR.sup.c,
--P(O).sub.2OR.sup.c, --CN, --NO.sub.2, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or mono- or bicyclic heteroaryl, or R.sup.4 and R.sup.5 taken
together with the ring to which they are attached form a
C.sub.5-C.sub.8 cycloalkyl, or a 5- to 8-membered heterocycloalkyl,
wherein each hydrogen atom in C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, mono- or bicyclic heteroaryl, C.sub.5-C.sub.8 cycloalkyl, or
5- to 8-membered heterocycloalkyl is independently optionally
substituted by deuterium, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, --OR.sup.e, --OC(O)R.sup.e,
--OC(O)NR.sup.eR.sup.f, --OC(.dbd.N)NR.sup.eR.sup.f,
--OS(O)R.sup.e, --OS(O).sub.2R.sup.e, --OS(O)NR.sup.eR.sup.f,
--OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e, --S(O)R.sup.e,
--S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.t, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2. In some embodiments, each R.sup.3, R.sup.4,
and R.sup.5 are each independently H, fluoro, chloro, bromo,
C.sub.1-C.sub.6 alkyl, --OH, --CN, --OC.sub.1-C.sub.6 alkyl,
--NHC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6 alkyl).sub.2 or
--CF.sub.3. In some embodiments, R.sup.3 is H, deuterium,
C.sub.1-C.sub.6 alkyl or halogen. In some embodiments, R.sup.3 is H
or F. In some embodiments, R.sup.4 is H, deuterium, C.sub.1-C.sub.6
alkyl or halogen. In some embodiments, R.sup.4 is H or Cl. In some
embodiments, R.sup.5 is F.
[0249] In some embodiments, R.sup.6 is H, deuterium,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to 7-membered
heterocycloalkyl, C.sub.6-C.sub.10 aryl, or mono- or bicyclic
heteroaryl, wherein each hydrogen atom in C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or mono- or bicyclic heteroaryl is independently optionally
substituted by deuterium, halogen, --OR.sup.e, --OC(O)R.sup.e,
--OC(O)NR.sup.eR.sup.f, --OC(.dbd.N)NR.sup.eR.sup.f,
--OS(O)R.sup.e, --OS(O).sub.2R.sup.e, --OS(O)NR.sup.eR.sup.f,
--OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e, --S(O)R.sup.e,
--S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2. In some embodiments, R.sup.6 is H,
C.sub.1-C.sub.6 alkyl or 3- to 7-membered heterocycloalkyl, wherein
each hydrogen atom in C.sub.1-C.sub.6 alkyl or 3- to 7-membered
heterocycloalkyl is independently optionally substituted by
halogen, --OH, --CN, --OC.sub.1-C.sub.6 alkyl, --NH.sub.2,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--CO.sub.2H, --C(O)OC.sub.1-C.sub.6 alkyl, --C(O)NH.sub.2,
--C(O)NH(C.sub.1-C.sub.6 alkyl), --C(O)N(C.sub.1-C.sub.6
alkyl).sub.2, C.sub.3-C.sub.6 cycloalkyl, or monocyclic 5- to
7-membered heterocycloalkyl.
[0250] In some embodiments, R.sup.7 and R.sup.8 combine to form a
C.sub.3-C.sub.7 cycloalkyl, a 5- to 8-membered heterocycloalkyl,
C.sub.6-C.sub.10 aryl, or 5- to 7-membered heteroaryl; wherein each
hydrogen atom in C.sub.3-C.sub.7 cycloalkyl, a 5- to 8-membered
heterocycloalkyl, C.sub.6-C.sub.10 aryl, or 5- to 7-membered
heteroaryl is independently optionally substituted by deuterium,
halogen, --OR.sup.e, --OC(O)R.sup.e, --OC(O)NR.sup.eR.sup.f,
--OC(.dbd.N)NR.sup.eR.sup.f, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e,
--OS(O)NR.sup.eR.sup.f, --OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e,
--S(O)R.sup.e, --S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.t, --NR.sup.eC(O)OR.sup.t,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.t,
--NR.sup.eS(O).sub.2R.sup.t, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, --P(O).sub.2OR.sup.e,
--CN, or --NO.sub.2.
[0251] In some embodiments, R.sup.7 and R.sup.8 combine to form a
C.sub.3-C.sub.7 cycloalkyl, a 5- to 8-membered heterocycloalkyl,
C.sub.6-C.sub.10 aryl, or 5- to 7-membered heteroaryl; wherein each
hydrogen atom in C.sub.3-C.sub.7 cycloalkyl, a 5- to 8-membered
heterocycloalkyl, C.sub.6-C.sub.10 aryl, or 5- to 7-membered
heteroaryl is independently optionally substituted by deuterium,
halogen, --OH, --OC.sub.1-C.sub.6 alkyl, --OC(O)C.sub.1-C.sub.6
alkyl, --OC(O)NH.sub.2, --OC(O)NH(C.sub.1-C.sub.6 alkyl),
--OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --OC(.dbd.N)NH.sub.2,
--OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl),
--OC(.dbd.N)N(C.sub.1-C.sub.6 alkyl).sub.2, --OS(O)C.sub.1-C.sub.6
alkyl, --OS(O).sub.2C.sub.1-C.sub.6 alkyl, --OS(O)NH.sub.2,
--OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --OS(O).sub.2NH.sub.2,
--OS(O).sub.2NH(C.sub.1-C.sub.6 alkyl),
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --SH,
--SC.sub.1-C.sub.6 alkyl, --S(O)C.sub.1-C.sub.6 alkyl,
--S(O).sub.2C.sub.1-C.sub.6 alkyl, --S(O)NH.sub.2,
--S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6
alkyl).sub.2, --S(O).sub.2NH.sub.2, --S(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --NH.sub.2,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)C.sub.1-C.sub.6 alkyl, --NHC(O)OH,
--NHC(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6 alkyl)C(O)OH,
--N(C.sub.1-C.sub.6 alkyl)C(O)OC.sub.1-C.sub.6 alkyl,
--NHC(O)NH.sub.2, --NHC(O)NH(C.sub.1-C.sub.6 alkyl),
--NHC(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --NHS(O)C.sub.1-C.sub.6
alkyl, --N(C.sub.1-C.sub.6 alkyl)S(O)C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl, --NHS(O)NH.sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)S(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2NH.sub.2, --NHS(O).sub.2NH(C.sub.1-C.sub.6 alkyl),
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --C(O)OC.sub.1-C.sub.6 alkyl,
--C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --P(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)(C.sub.1-C.sub.6 alkyl).sub.2,
--P(O).sub.2(C.sub.1-C.sub.6 alkyl).sub.2, --P(O)NH.sub.2,
--P(O)NH(C.sub.1-C.sub.6 alkyl), --P(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --P(O).sub.2NH.sub.2, --P(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --P(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --P(O)OH,
--P(O)OC.sub.1-C.sub.6 alkyl, --P(O).sub.2OH,
--P(O).sub.2OC.sub.1-C.sub.6 alkyl, --CN, or --NO.sub.2.
[0252] In some embodiments, R.sup.7 and R.sup.8 combine to form a
5- or 6-membered cycloalkyl, wherein each hydrogen atom in the 4-,
5- or 6-membered cycloalkyl is independently optionally substituted
by deuterium, halogen, --OH, --CN, --OC.sub.1-C.sub.6 alkyl,
--OC.sub.1-C.sub.6 alkyl(C.sub.6-C.sub.10 aryl), --NH.sub.2,
--OC(O)C.sub.1-C.sub.6 alkyl, --OC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --OC(O)NH(C.sub.1-C.sub.6 alkyl), --OC(O)NH.sub.2,
--OC(.dbd.N)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl), --OC(.dbd.N)NH.sub.2,
--OS(O)C.sub.1-C.sub.6 alkyl, --OS(O).sub.2C.sub.1-C.sub.6 alkyl,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)C.sub.1-C.sub.6 alkyl, --NHC(O)NH.sub.2,
--NHC(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --NHC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --NHC(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)OC.sub.1-C.sub.6 alkyl, --NHC(O)OH, --N(C.sub.1-C.sub.6
alkyl)C(O)OH, --NHS(O)C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl, --NHS(O)NH.sub.2,
--NHS(O).sub.2NH.sub.2, --N(C.sub.1-C.sub.6 alkyl)S(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH.sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --NHS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --CO.sub.2H, --C(O)OC.sub.1-C.sub.6
alkyl, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --SC.sub.1-C.sub.6 alkyl,
--S(O)C.sub.1-C.sub.6 alkyl, --S(O).sub.2C.sub.1-C.sub.6 alkyl,
--S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --S(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --S(O)NH.sub.2,
--S(O).sub.2NH.sub.2, --OS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --OS(O)NH.sub.2, --OS(O).sub.2NH.sub.2, --P(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.3-C.sub.6
cycloalkyl, or 3- to 7-membered heterocycloalkyl.
[0253] In some embodiments, R.sup.7 and R.sup.8 combine to form a
3-, 4-, 5- or 6-membered heterocycloalkyl, wherein each hydrogen
atom in the 3-, 4-, 5- or 6-membered heterocycloalkyl is
independently optionally substituted by deuterium, halogen, --OH,
--CN, --OC.sub.1-C.sub.6 alkyl, --OC.sub.1-C.sub.6
alkyl(C.sub.6-C.sub.10 aryl), --NH.sub.2, --OC(O)C.sub.1-C.sub.6
alkyl, --OC(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(O)NH(C.sub.1-C.sub.6 alkyl), --OC(O)NH.sub.2,
--OC(.dbd.N)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl), --OC(.dbd.N)NH.sub.2,
--OS(O)C.sub.1-C.sub.6 alkyl, --OS(O).sub.2C.sub.1-C.sub.6 alkyl,
--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)C.sub.1-C.sub.6 alkyl, --NHC(O)NH.sub.2,
--NHC(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1-C.sub.6 alkyl), --NHC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --NHC(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)OC.sub.1-C.sub.6 alkyl, --NHC(O)OH, --N(C.sub.1-C.sub.6
alkyl)C(O)OH, --NHS(O)C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl, --NHS(O)NH.sub.2,
--NHS(O).sub.2NH.sub.2, --N(C.sub.1-C.sub.6 alkyl)S(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH.sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --NHS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --CO.sub.2H, --C(O)OC.sub.1-C.sub.6
alkyl, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --SC.sub.1-C.sub.6 alkyl,
--S(O)C.sub.1-C.sub.6 alkyl, --S(O).sub.2C.sub.1-C.sub.6 alkyl,
--S(O)NH(C.sub.1-C.sub.6 alkyl), --S(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --S(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2, --S(O)NH.sub.2,
--S(O).sub.2NH.sub.2, --OS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--OS(O)NH(C.sub.1-C.sub.6 alkyl), --OS(O).sub.2NH(C.sub.1-C.sub.6
alkyl), --OS(O)NH.sub.2, --OS(O).sub.2NH.sub.2, --P(C.sub.1-C.sub.6
alkyl).sub.2, --P(O)(C.sub.1-C.sub.6 alkyl).sub.2, C.sub.3-C.sub.6
cycloalkyl, or 3- to 7-membered heterocycloalkyl. In some
embodiments, R.sup.7 and R.sup.8 combine to form a tetrahydrofuran
ring. In some embodiments, R.sup.7 and R.sup.8 combine to form a
cyclopentane ring.
[0254] In some embodiments, Y is --O--, --S--, --NR.sup.9, or
--CR.sup.9R.sup.10--. In some embodiments, Y is --O--.
[0255] In some embodiments, R.sup.9 and R.sup.10 are each
independently H, deuterium, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom
in C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6 cycloalkyl, 3- to 7-membered
heterocycloalkyl, C.sub.6-C.sub.10 aryl, or mono- or bicyclic
heteroaryl is optionally substituted by a halogen, --OR.sup.e,
--OC(O)R.sup.e, --OC(O)NR.sup.eR.sup.f,
--OC(.dbd.N)NR.sup.eR.sup.f, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e,
--OS(O)NR.sup.eR.sup.f, --OS(O).sub.2NR.sup.eR.sup.f, --SR.sup.e,
--S(O)R.sup.e, --S(O).sub.2R.sup.e, --S(O)NR.sup.eR.sup.f,
--S(O).sub.2NR.sup.eR.sup.f, --NR.sup.eR.sup.f,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.eR.sup.f, --NR.sup.eS(O)R.sup.t,
--NR.sup.eS(O).sub.2R.sup.t, --NR.sup.eS(O)NR.sup.eR.sup.f,
--NR.sup.eS(O).sub.2NR.sup.eR.sup.f, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.eR.sup.f, --PR.sup.eR.sup.f, --P(O)R.sup.eR.sup.f,
--P(O).sub.2R.sup.eR.sup.f, --P(O)NR.sup.eR.sup.f,
--P(O).sub.2NR.sup.eR.sup.f, --P(O)OR.sup.e, or
--P(O).sub.2OR.sup.e.
[0256] In some embodiments, R.sup.9 and R.sup.10 are each
independently H, deuterium, halogen, or C.sub.1-C.sub.6 alkyl,
wherein each hydrogen atom in C.sub.1-C.sub.6 alkyl is optionally
substituted by a halogen, --OH, --OC.sub.1-C.sub.6 alkyl,
--OC(O)C.sub.1-C.sub.6 alkyl, --OC(O)N(C.sub.1-C.sub.6
alkyl).sub.2, --OC(O)NH(C.sub.1-C.sub.6 alkyl), --OC(O)NH.sub.2,
--OC(.dbd.N)N(C.sub.1-C.sub.6 alkyl).sub.2,
--OC(.dbd.N)NH(C.sub.1-C.sub.6 alkyl), --OC(.dbd.N)NH.sub.2,
--OS(O)C.sub.1-C.sub.6 alkyl, --OS(O).sub.2C.sub.1-C.sub.6 alkyl,
--OS(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --OS(O)NH(C.sub.1-C.sub.6
alkyl), --OS(O)NH.sub.2, --OS(O).sub.2N(C.sub.1-C.sub.6
alkyl).sub.2, --OS(O).sub.2NH(C.sub.1-C.sub.6 alkyl),
--OS(O).sub.2NH.sub.2, --SH, --SC.sub.1-C.sub.6 alkyl,
--S(O)C.sub.1-C.sub.6 alkyl, --S(O).sub.2C.sub.1-C.sub.6 alkyl,
--S(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --S(O)NH(C.sub.1-C.sub.6
alkyl), --S(O)NH.sub.2, --S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--S(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --S(O).sub.2NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl).sub.2, --NH(C.sub.1-C.sub.6 alkyl),
--NH.sub.2, --N(C.sub.1-C.sub.6 alkyl)C(O)C.sub.1-C.sub.6 alkyl,
--NHC(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)C(O)OC.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6 alkyl)C(O)OH,
--NHC(O)OC.sub.1-C.sub.6 alkyl, --NHC(O)OH, --N(C.sub.1-C.sub.6
alkyl)C(O)N(C.sub.1C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)C(O)NH(C.sub.1C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)C(O)NH.sub.2, --NHC(O)N(C.sub.1C.sub.6 alkyl).sub.2,
--NHC(O)NH(C.sub.1C.sub.6 alkyl), --NHC(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O)C.sub.1-C.sub.6 alkyl,
--NHS(O)C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O).sub.2C.sub.1-C.sub.6 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.6
alkyl)S(O)N(C.sub.1-C.sub.6 alkyl).sub.2, --N(C.sub.1-C.sub.6
alkyl)S(O)NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)S(O)NH.sub.2, --NHS(O)N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O)NH(C.sub.1-C.sub.6 alkyl), --NHS(O)NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl)S(O).sub.2NH.sub.2,
--NHS(O).sub.2N(C.sub.1-C.sub.6 alkyl).sub.2,
--NHS(O).sub.2NH(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2NH.sub.2,
--C(O)C.sub.1-C.sub.6 alkyl, --C(O)OC.sub.1-C.sub.6 alkyl,
--C(O)N(C.sub.1-C.sub.6 alkyl)z, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)NH.sub.2, --P(C.sub.1-C.sub.6 alkyl)z, --P(O)(C.sub.1-C.sub.6
alkyl)z, --P(O).sub.2(C.sub.1-C.sub.6 alkyl).sub.2,
--P(O)N(C.sub.1-C.sub.6 alkyl)z, --P(O).sub.2N(C.sub.1-C.sub.6
alkyl)z, --P(O)OC.sub.1-C.sub.6 alkyl, or
--P(O).sub.2OC.sub.1-C.sub.6 alkyl.
[0257] In some embodiments, each R.sup.a, R.sup.b, R.sup.c,
R.sup.d, R.sup.e, and R.sup.f is independently selected from the
group consisting of H, deuterium, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6
cycloalkyl, 3- to 7-membered heterocycloalkyl, C.sub.6-C.sub.10
aryl, 5- to 7-membered heteroaryl.
[0258] In some embodiments, p is 1, 2, 3, or 4. In some
embodiments, p is 1.
[0259] In some embodiments, t is 1, 2, 3, 4, or 5. In some
embodiments, t is 3. In some embodiments, t is 4. In some
embodiments, t is 3 or 4.
[0260] In some embodiments, n, if present, is 1, 2, or 3. In some
embodiments, n is 2. In some embodiments, n is 3. In some
embodiments, n is 2 or 3.
[0261] The following represent illustrative embodiments of
compounds of the formula I, II, III, and IV:
TABLE-US-00001 Compound Structure Name 1 ##STR00039##
(3aR,11S,20aS)-7-fluoro-11-methyl-
2,3,3a,12,13,20a-hexahydro-1H,5H-17,19-
(metheno)cyclopenta[5,6][l,4]oxazino[3,4- i]pyrazolo[4,3-
f[1,4,8,10]benzoxatriazacyclotridecin- 14(11H)-one 2 ##STR00040##
(7S)-3-amino-11-fluoro-7-methyl-4-oxo-14-
(propan-2-yl)-4,5,6,7,13,14-hexahydro-1,15- ethenopyrazolo[4,3-
f][1,4,8,10]benzoxatriazacyclotridecine-12- carbonitrile 3
##STR00041## (3aR,11S,20aS)-7,9-difluoro-11-methyl-
2,3,3a,12,13,20a-hexahydro-1H,5H-17,19-
(metheno)cyclopenta[5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-
f][1,4,8,10]benzoxatriazacyclotridecin- 14(11H)-one 4 ##STR00042##
(3aR,11S,20aR)-7-fluoro-11-methyl-
1,3,3a,12,13,20a-hexahydro-5H-17,19-
(metheno)furo[3',4':5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-
f][1,4,8,10]benzoxatriazacyclotridecin- 14(11H)-one 5 ##STR00043##
(3aR,11S,20aS)-7-fluoro-11-methyl-
2,3,3a,12,13,20a-hexahydro-1H,5H-17,19-
(metheno)cyclopenta[5,6][1,4]oxazino[3,4-
i]pyrazolo[4,3-f]pyrido[3,2-l] [1,4,8,10]oxatriazacyclotridecin-
14(11H)-one 6 ##STR00044## (3aR,12R,20aS)-7-fluoro-12-methyl-
2,3,3a,12,13,20a-hexahydro-1H,5H-17,19-
(metheno)cyclopenta[5,6][1,4]oxazino[3,4-
i]pyrazolo[4,3-f]pyrido[3,2-l] [1,4,8,10]oxatriazacyclotridecin-
14(11H)-one 7 ##STR00045## (3aR,12R,20aS)-7,9-difluoro-12-methyl-
2,3,3a,12,13,20a-hexahydro-1H,5H-17,19-
(metheno)cyclopenta[5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-f]
[1,4,8,10]benzoxatriazacyclotridecin- 14(11H)-one 8 ##STR00046##
(2aR,10S,19aS)-6-fluoro-10-methyl-
1,2,2a,11,12,19a-hexahydro-4H-16,18-
(metheno)cyclobuta[5,6][1,4]oxazino[3,4-
i]pyrazolo[4,3-f]pyrido[3,2-l] [1,4,8,10]oxatriazacyclotridecin-
13(10H)-one 9 ##STR00047## (2aS,10S,19aR)-6-fluoro-10-methyl-
1,2,2a,11,12,19a-hexahydro-4H-16,18-
(metheno)cyclobuta[5,6][1,4]oxazino[3,4-
i]pyrazolo[4,3-f]pyrido[3,2-l] [1,4,8,10]oxatriazacyclotridecin-
13(10H)-one 10 ##STR00048## (2aR,11R,19aS)-6-fluoro-11-methyl-
1,2,2a,11,12,19a-hexahydro-4H-16,18-
(metheno)cyclobuta[5,6][1,4]oxazino[3,4-
i]pyrazolo[4,3-f]pyrido[3,2-l] [1,4,8,10]oxatriazacyclotridecin-
13(10H)-one 11 ##STR00049## (2aS,11R,19aR)-6-fluoro-11-methyl-
1,2,2a,11,12,19a-hexahydro-4H-16,18-
(metheno)cyclobuta[5,6][1,4]oxazino[3,4-
i]pyrazolo[4,3-f]pyrido[3,2-l] [1,4,8,10]oxatriazacyclotridecin-
13(10H)-one 12 ##STR00050## (4aR,12S,21aS)-8-fluoro-12-methyl-
1,2,3,4,4a,13,14,21a-octahydro-6H-18,20-
(metheno)pyrazolo[4',3':6,7]pyrido[3',2':12,l
3][1,4,8,10]oxatriazacyclotridecino[9,10-
c][1,4]benzoxazin-15(12H)-one 13 ##STR00051##
(4aR,13R,21aS)-8-fluoro-13-methyl-
1,2,3,4,4a,13,14,21a-octahydro-6H-18,20-
(metheno)pyrazolo[4',3':6,7]pyrido[3',2':12,
13][1,4,8,10]oxatriazacyclotridecino[9,10-
c][1,4]benzoxazin-15(12H)-one 14 ##STR00052##
(3aR,12R,20aS)-12-cyclopropyl-7-fluoro-
2,3,3a,12,13,20a-hexahydro-1H,5H-17,19-
(metheno)cyclobuta[5,6][1,4]oxazino[3,4-
i]pyrazolo[4,3-f]pyrido[3,2-l] [1,4,8,10]oxatriazacyclotridecin-
13(10H)-one 15 ##STR00053## (3aR,11S,21aS)-7-fluoro-11-methyl-
2,3,3a,11,12,13,14,21a-octahydro- 1H,5H,15H-18,20-
(metheno)cyclobuta[5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3-b]
[1,5,7,11]oxatriazacyclotetradecin-15-one 16 ##STR00054##
(3aR,13R,21aS)-7-fluoro-13-methyl-
2,3,3a,11,12,13,14,21a-octahydro- 1H,5H,15H-18,20-
(metheno)cyclobuta[5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3-b]
[1,5,7,11]oxatriazacyclotetradecin-15-one 17 ##STR00055##
(3aR,12S,21aS)-7-fluoro-12-methyl-
2,3,3a,11,12,13,14,21a-octahydro- 1H,5H,15H-18,20-
(metheno)cyclopenta[5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3-b]
[1,5,7,11]oxatriazacyclotetradecin-15-one 18 ##STR00056##
(3a'R,20a'S)-7'-fluoro- 1'H,2'H,3'H,3a'H,5'H,11'H,13'H,14'H,
20a'H,spiro[cyclopropane-1,12'-[10,
20]dioxa[4,9,13,16,17,18]hexaaza[17,19]
(metheno)cyclopenta[5,6][1,4]oxazino[3,4-
i]pyrazolo[4,3-f]pyrido[3,2-l]
[1,4,8,10]oxatriazacyclotridecin]-14'-one 19 ##STR00057##
(3aR,21aS)-7-fluoro-2,3,3a,11,12,13,14,21a-
octahydro-1H,5H,15H-18,20-
(metheno)cyclopenta[5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3-b]
[1,5,7,11]oxatriazacyclotetradecin-15-one 20 ##STR00058##
(3a'R,21a'S)-7'-fluoro- 1'H,2'H,3'H,3a'H,5'H,11'H,13'H,14'H,15'H,
21a'H,spiro[cyclopropane-1,12'-
[10,21]dioxa[4,9,14,17,18,19]hexaaza[18,20]
(metheno)cyclopenta[5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclotetradecin]-
15'-one 21 ##STR00059## (3aR,20aS)-7-fluoro-12,12-dimethyl-
2,3,3a,12,13,20a-hexahydro-1H,5H,17,19-
(metheno)cyclopenta[5,6][1,4]oxazino[3,4-
i]pyrazolo[4,3-f]pyrido[3,2-l] [1,4,8,10]oxatriazacyclotridecin-
14(11H)-one 22 ##STR00060## (3a'R,20a'S)-7'-fluoro-
1'H,2'H,3'H,3a'H,5'H,11'H,13'H,14'H,20a'H- spiro[cyclobutane-1,12'-
[10,20]dioxa[4,9,13,16,17,18]hexaaza[17,19]
(metheno)cyclopenta[5,6][1,4]oxazino[3,4-
i]pyrazolo[4,3-f]pyrido[3,2-
i][1,4,8,10]oxatriazacyclotridecin]-14'-oneo 23 ##STR00061##
(3a'R,21a'S)-7'-fluoro- 1'H,2'H,3'H,3a'H,5'H,11'H,13'H,14'H,15'H,
21a'H-spiro[cyclobutane-1,12'-
[10,21]dioxa[4,9,14,17,18,19]hexaaza[18,20]
(metheno)cyclopenta[5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecin]-
15'-one 24 ##STR00062## (3aS,11aR,14aS,21aR)-18-fluoro-
2,3,3a,11,11a,12,13,14,14a,21a-decahydro- 1H,10H,20H-7,5-
(metheno)cyclopenta[b]cyclopenta[5,6][1,4]
oxazino[3,4-i]pyrazolo[4,3-f]pyrido[3,2-l]
[1,4,8,10]oxatriazacyclotridecin-10-one 25 ##STR00063##
(3a'R,20a'S)-3,3,7'-trifluoro-
1'H,2'H,3'H,3a'H,5'H,11'H,13'H,14'H,20a'H- spiro[cyclobutane-1,12'-
[10,20]dioxa[4,9,13,16,17,18]hexaaza[17,19]
(metheno)cyclopenta[5,6][1,4]oxazino[3,4-
i]pyrazolo[4,3-f]pyrido[3,2-
l][1,4,8,10]oxatriazacyclotridecin]-14'-one 26 ##STR00064##
(3a'R,20a'S)-7'-fluoro- 1'H,2'H,3'H,3a'H,5'H,11'H,13'H,14'H,20a'H-
spiro[cyclobutane-1,12'-
[10,20]dioxa[4,9,13,16,17,18]hexaaza[17,19]
(metheno)cyclopenta[5,6][1,4]oxazino[3,4-
i]pyrazolo[4,3-f]pyrido[3,2-
l][1,4,8,10]oxatriazacyclotridecin]-14'-one 27 ##STR00065##
(3aR,21aS)-7-fluoro-12,12-dimethyl-
2,3,3a,11,12,13,14,21a-octahydro- 1H,5H,15H-18,20-
(metheno)cyclobuta[5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3-b]
[1,5,7,11]oxatriazacyclotetradecin-15-one 28 ##STR00066##
(3aR,13S,21aS)-7-fluoro-13-methyl-
2,3,3a,11,12,13,14,21a-octahydro- 1H,5H,15H-18,20-
(metheno)cyclopenta[5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3-b]
[1,5,7,11]oxatriazacyclotetradecin-15-one 29 ##STR00067##
(3aR,21aS)-7-fluoro-12-methyl- 2,3,3a,11,12,13,14,21a-octahydro-
1H,5H,15H-18,20- (metheno)cyclopenta[5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3-b]
[1,5,7,11]oxatriazacyclotetradecin-15-one 30 ##STR00068##
(3aR,11S,20aR)-7-fluoro-11-methyl-
1,3,3a,12,13,20a-hexahydro-5H-17,19-
(metheno)furo[3',4':5,6][1,4]oxazino[3,4-
i]pyrazolo[4,3-f]pyrido[3,2-l]
[1,4,8,10]oxatriazacyclotridecin-14(11H)- one 31 ##STR00069##
(3aS,11S,20aS)-7-fluoro-11-methyl-
1,3,3a,12,13,20a-hexahydro-5H-17,19-
(metheno)furo[3',4':5,6][1,4]oxazino[3,4-
i]pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]
oxatriazacyclotridecin-14(11H)-one 32 ##STR00070##
(3aR,12S,21aS)-7-fluoro-12-hydroxy-
2,3,3a,11,12,13,14,21a-octahydro-1H,5H,
15H-18,20-(metheno)cyclopenta [5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3-b]
[1,5,7,11]oxatriazacyclotetradecin-15-one 33 ##STR00071##
(3aR,21aS)-7-fluoro-12,12-dihydroxy-
2,3,3a,11,12,13,14,21a-octahydro-
1H,5H,15H-18,20-(metheno)cyclopenta [5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3-b]
[1,5,7,11]oxatriazacyclotetradecin-15-one 34 ##STR00072##
(3aR,21aS)-7-fluoro-13,13-dimethyl-
2,3,3a,11,12,13,14,21a-octahydro-
1H,5H,15H-18,20-(metheno)cyclopenta [5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclotetradecin-
15-one 35 ##STR00073## (3aR,11R,21aS)-7-fluoro-11-methyl-
2,3,3a,11,12,13,14,21a-octahydro-
1H,5H,15H-18,20-(metheno)cyclopenta [5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclotetradecin-
15-one 36 ##STR00074## (3aR,11S,20aS)-2-acetyl-7-fluoro-11-
methyl-2,3,3a,11,12,13,20a-hexahydro-
1H,5H-17,19-(metheno)pyrazolo[4,3-f]
pyrido[2,3-l]pyrrolo[3',4':5,6][1,4] oxazino[3,4-i][1,4,8,10]
oxatriazacyclotridecin-14(11H)-one 37 ##STR00075##
(3aS,11S,20aR)-2-acetyl-7-fluoro-11-
methyl-2,3,3a,12,13,20a-hexahydro-
1H,5H-17,19-(metheno)pyrazolo[4,3-f]
pyrido[3,2-l]pyrrolo[3',4':5,6][1,4] oxazino[3,4-i][1,4,8,10]
oxatriazacyclotridecin-14(11H)-one 38 ##STR00076##
(3aR,12S,21aS)-7,12-difluoro- 2,3,3a,11,12,13,14,21a-octahydro-
1H,5H,15H-18,20-(metheno)cyclopenta [5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3-b]
[1,5,7,11]oxatriazacyclotetradecin-15- one 39 ##STR00077##
(3aR,12R,21aS)-7,12-difluoro- 2,3,3a,11,12,13,14,21a-octahydro-
1H,5H,15H-18,20-(metheno)cyclopenta [5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3-b]
[1,5,7,11]oxatriazacyclotetradecin-15-one 40 ##STR00078##
(3aR,21aS)-7,12,12-trifluoro- 2,3,3a,11,12,13,14,21a-octahydro-
1H,5H,15H-18,20-(metheno)cyclopenta [5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3-b]
[1,5,7,11]oxatriazacyclotetradecin-15-one 41 ##STR00079##
(3aR,11R,14S,22aS)-7-fluoro- 2,3,3a,12,13,14,15,22a-octahydro-
1H,5H,11,14-methano-19,21-
(metheno)cyclopenta[5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclopentadecin-
16(11H)-one 42 ##STR00080## (3aR,11S,14R,22aS)-7-fluoro-
2,3,3a,12,13,14,15,22a-octahydro- 1H,5H,11,14-methano-19,21-
(metheno)cyclopenta[5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3-b] [1,5,7,11]oxatriazacyclopentadecin-
16(11H)-one 43 ##STR00081## (3aR,12R,21aS)-7-fluoro-12-hyroxy-
2,3,3a,11,12,13,14,21a-octahydro-
1H,5H,15H-18,20-(metheno)cyclopenta [5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3-b]
[1,5,7,11]oxatriazacyclotetradecin-15-one 44 ##STR00082##
(3aS,11R,20aR)-7-fluoro-11-methyl- 2,3,3a,12,13,20a-hexahydro-
1H,5H,17,19- (metheno)cyclopenta[5,6][1,4]oxazino[3,4-
i]pyrazolo[4,3-f]pyrido[3,2-l]
[1,4,8,10]oxatriazacyclotridecin-14(11H)-one 45 ##STR00083##
(3a'R,21a'S)-7'-fluoro- 1'H,2'H,3'H,3a'H,5'H,11'H,12'H,14'H,15'H,
21a'H-spiro[cyclobutane-1,13'-
[10,21]dioxa[4,9,14,17,18,19]hexaaza[18,20]
(metheno)cyclopenta[5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3-
b][1,5,7,11]oxatriazacyclotetradecin]-15'-one 46 ##STR00084##
(3aR,11s,13S,21aS)-7-fluoro- 2,3,3a,12,13,14,15,21a-octahydro-
1H,5H,11H-11,13-metheno-18,20-
(metheno)cyclopenta[5,6][1,4]oxazino[4,3-
e]pyrazolo[3,4-h]pyrido[2,3- b][1,5,7,11]oxatriazacyclotetradecine
47 ##STR00085## (3aR,12S,20aS)-12-difluoromethyl-7-
fluoro-2,3,3a,12,13,20a-hexahydro- 1H,5H,17,19-(metheno)
cyclopenta[5,6][1,4]oxazino[3,4- i]pyrazolo[4,3-f]pyrido[3,2-l]
[1,4,8,10]oxatriazacyclotridecin-14(11H)-one 48 ##STR00086##
(3aR,12S,20aS)-7-fluoro-12- (trifluoromethyl)-2,3,3a,12,13,20a-
hexahydro-1H,5H,17,19- (metheno)cyclopenta[5,6][1,4]oxazino[3,4-
i]pyrazolo[4,3-f]pyrido[3,2- b][1,4,8,10]oxatriazacyclotridecin-
14(11H)-one
49 ##STR00087## (3aR,11S,20aS)-7-fluoro-11-
(hydroxymethyl)-2,3,3a,12,13,20a- hexahydro-1H,5H,17,19-
(metheno)cyclopenta[5,6][1,4]oxazino
[3,4-i]pyrazolo[4,3-f]pyrido[3,2-
l][1,4,8,10]oxatriazacyclotridecin- 14(11H)-one
[0262] Those skilled in the art will recognize that the species
listed or illustrated herein are not exhaustive, and that
additional species within the scope of these defined terms may also
be selected.
Pharmaceutical Compositions
[0263] For treatment purposes, pharmaceutical compositions
comprising the compounds described herein may further comprise one
or more pharmaceutically-acceptable excipients. A
pharmaceutically-acceptable excipient is a substance that is
non-toxic and otherwise biologically suitable for administration to
a subject. Such excipients facilitate administration of the
compounds described herein and are compatible with the active
ingredient. Examples of pharmaceutically-acceptable excipients
include stabilizers, lubricants, surfactants, diluents,
anti-oxidants, binders, coloring agents, bulking agents,
emulsifiers, or taste-modifying agents. In preferred embodiments,
pharmaceutical compositions according to the invention are sterile
compositions. Pharmaceutical compositions may be prepared using
compounding techniques known or that become available to those
skilled in the art.
[0264] Sterile compositions are also contemplated by the invention,
including compositions that are in accord with national and local
regulations governing such compositions.
[0265] The pharmaceutical compositions and compounds described
herein may be formulated as solutions, emulsions, suspensions, or
dispersions in suitable pharmaceutical solvents or carriers, or as
pills, tablets, lozenges, suppositories, sachets, dragees,
granules, powders, powders for reconstitution, or capsules along
with solid carriers according to conventional methods known in the
art for preparation of various dosage forms. Pharmaceutical
compositions of the invention may be administered by a suitable
route of delivery, such as oral, parenteral, rectal, nasal,
topical, or ocular routes, or by inhalation. Preferably, the
compositions are formulated for intravenous or oral
administration.
[0266] For oral administration, the compounds the invention may be
provided in a solid form, such as a tablet or capsule, or as a
solution, emulsion, or suspension. To prepare the oral
compositions, the compounds of the invention may be formulated to
yield a dosage of, e.g., from about 0.1 mg to 1 g daily, or about 1
mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to
1 g daily. Oral tablets may include the active ingredient(s) mixed
with compatible pharmaceutically acceptable excipients such as
diluents, disintegrating agents, binding agents, lubricating
agents, sweetening agents, flavoring agents, coloring agents and
preservative agents. Suitable inert fillers include sodium and
calcium carbonate, sodium and calcium phosphate, lactose, starch,
sugar, glucose, methyl cellulose, magnesium stearate, mannitol,
sorbitol, and the like. Exemplary liquid oral excipients include
ethanol, glycerol, water, and the like. Starch,
polyvinyl-pyrrolidone (PVP), sodium starch glycolate,
microcrystalline cellulose, and alginic acid are exemplary
disintegrating agents. Binding agents may include starch and
gelatin. The lubricating agent, if present, may be magnesium
stearate, stearic acid, or talc. If desired, the tablets may be
coated with a material such as glyceryl monostearate or glyceryl
distearate to delay absorption in the gastrointestinal tract, or
may be coated with an enteric coating.
[0267] Capsules for oral administration include hard and soft
gelatin capsules. To prepare hard gelatin capsules, active
ingredient(s) may be mixed with a solid, semi-solid, or liquid
diluent. Soft gelatin capsules may be prepared by mixing the active
ingredient with water, an oil, such as peanut oil or olive oil,
liquid paraffin, a mixture of mono and di-glycerides of short chain
fatty acids, polyethylene glycol 400, or propylene glycol.
[0268] Liquids for oral administration may be in the form of
suspensions, solutions, emulsions, or syrups, or may be lyophilized
or presented as a dry product for reconstitution with water or
other suitable vehicle before use. Such liquid compositions may
optionally contain: pharmaceutically-acceptable excipients such as
suspending agents (for example, sorbitol, methyl cellulose, sodium
alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose,
aluminum stearate gel and the like); non-aqueous vehicles, e.g.,
oil (for example, almond oil or fractionated coconut oil),
propylene glycol, ethyl alcohol, or water; preservatives (for
example, methyl or propyl p-hydroxybenzoate or sorbic acid);
wetting agents such as lecithin; and, if desired, flavoring or
coloring agents.
[0269] For parenteral use, including intravenous, intramuscular,
intraperitoneal, intranasal, or subcutaneous routes, the agents of
the invention may be provided in sterile aqueous solutions or
suspensions, buffered to an appropriate pH and isotonicity or in
parenterally acceptable oil. Suitable aqueous vehicles include
Ringer's solution and isotonic sodium chloride. Such forms may be
presented in unit-dose form such as ampoules or disposable
injection devices, in multi-dose forms such as vials from which the
appropriate dose may be withdrawn, or in a solid form or
pre-concentrate that can be used to prepare an injectable
formulation. Illustrative infusion doses range from about 1 to 1000
.mu.g/kg/minute of agent admixed with a pharmaceutical carrier over
a period ranging from several minutes to several days.
[0270] For nasal, inhaled, or oral administration, the inventive
pharmaceutical compositions may be administered using, for example,
a spray formulation also containing a suitable carrier. The
inventive compositions may be formulated for rectal administration
as a suppository.
[0271] For topical applications, the compounds of the present
invention are preferably formulated as creams or ointments or a
similar vehicle suitable for topical administration. For topical
administration, the inventive compounds may be mixed with a
pharmaceutical carrier at a concentration of about 0.1% to about
10% of drug to vehicle. Another mode of administering the agents of
the invention may utilize a patch formulation to effect transdermal
delivery.
[0272] As used herein, the terms "treat" or "treatment" encompass
both "preventative" and "curative" treatment. "Preventative"
treatment is meant to indicate a postponement of development of a
disease, a symptom of a disease, or medical condition, suppressing
symptoms that may appear, or reducing the risk of developing or
recurrence of a disease or symptom. "Curative" treatment includes
reducing the severity of or suppressing the worsening of an
existing disease, symptom, or condition. Thus, treatment includes
ameliorating or preventing the worsening of existing disease
symptoms, preventing additional symptoms from occurring,
ameliorating or preventing the underlying systemic causes of
symptoms, inhibiting the disorder or disease, e.g., arresting the
development of the disorder or disease, relieving the disorder or
disease, causing regression of the disorder or disease, relieving a
condition caused by the disease or disorder, or stopping the
symptoms of the disease or disorder.
[0273] The term "subject" refers to a mammalian patient in need of
such treatment, such as a human.
[0274] Exemplary diseases include cancer, pain, neurological
diseases, autoimmune diseases, and inflammation. Cancer includes,
for example, lung cancer, colon cancer, breast cancer, prostate
cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and
esophago-gastric cancers, glioblastoma, head and neck cancers,
inflammatory myofibroblastic tumors, and anaplastic large cell
lymphoma. Pain includes, for example, pain from any source or
etiology, including cancer pain, pain from chemotherapeutic
treatment, nerve pain, pain from injury, or other sources.
Autoimmune diseases include, for example, rheumatoid arthritis,
Sjogren syndrome, Type I diabetes, and lupus. Exemplary
neurological diseases include Alzheimer's Disease, Parkinson's
Disease, Amyotrophic lateral sclerosis, and Huntington's disease.
Exemplary inflammatory diseases include atherosclerosis, allergy,
and inflammation from infection or injury.
[0275] In one aspect, the compounds and pharmaceutical compositions
of the invention specifically target receptor tyrosine kinases, in
particular RET. In another aspect, the compounds and pharmaceutical
compositions of the invention specifically target non-receptor
tyrosine kinases, in particular SRC. In yet another aspect, the
compounds and pharmaceutical compositions of the invention
specifically target receptor tyrosine kinases and non-receptor
tyrosine kinases, such as RET and SRC, respectively. Thus, these
compounds and pharmaceutical compositions can be used to prevent,
reverse, slow, or inhibit the activity of one or more of these
kinases. In preferred embodiments, methods of treatment target
cancer. In other embodiments, methods are for treating lung cancer
or non-small cell lung cancer.
[0276] In the inhibitory methods of the invention, an "effective
amount" means an amount sufficient to inhibit the target protein.
Measuring such target modulation may be performed by routine
analytical methods such as those described below. Such modulation
is useful in a variety of settings, including in vitro assays. In
such methods, the cell is preferably a cancer cell with abnormal
signaling due to upregulation of RET and/or SRC.
[0277] In treatment methods according to the invention, an
"effective amount" means an amount or dose sufficient to generally
bring about the desired therapeutic benefit in subjects needing
such treatment. Effective amounts or doses of the compounds of the
invention may be ascertained by routine methods, such as modeling,
dose escalation, or clinical trials, taking into account routine
factors, e.g., the mode or route of administration or drug
delivery, the pharmacokinetics of the agent, the severity and
course of the infection, the subject's health status, condition,
and weight, and the judgment of the treating physician. An
exemplary dose is in the range of about from about 0.1 mg to 1 g
daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily,
or about 250 mg to 1 g daily. The total dosage may be given in
single or divided dosage units (e.g., BID, TID, QID).
[0278] Once improvement of the patient's disease has occurred, the
dose may be adjusted for preventative or maintenance treatment. For
example, the dosage or the frequency of administration, or both,
may be reduced as a function of the symptoms, to a level at which
the desired therapeutic or prophylactic effect is maintained. Of
course, if symptoms have been alleviated to an appropriate level,
treatment may cease. Patients may, however, require intermittent
treatment on a long-term basis upon any recurrence of symptoms.
Patients may also require chronic treatment on a long-term
basis.
Drug Combinations
[0279] The inventive compounds described herein may be used in
pharmaceutical compositions or methods in combination with one or
more additional active ingredients in the treatment of the diseases
and disorders described herein. Further additional active
ingredients include other therapeutics or agents that mitigate
adverse effects of therapies for the intended disease targets. Such
combinations may serve to increase efficacy, ameliorate other
disease symptoms, decrease one or more side effects, or decrease
the required dose of an inventive compound. The additional active
ingredients may be administered in a separate pharmaceutical
composition from a compound of the present invention or may be
included with a compound of the present invention in a single
pharmaceutical composition. The additional active ingredients may
be administered simultaneously with, prior to, or after
administration of a compound of the present invention.
[0280] Combination agents include additional active ingredients are
those that are known or discovered to be effective in treating the
diseases and disorders described herein, including those active
against another target associated with the disease. For example,
compositions and formulations of the invention, as well as methods
of treatment, can further comprise other drugs or pharmaceuticals,
e.g., other active agents useful for treating or palliative for the
target diseases or related symptoms or conditions. For cancer
indications, additional such agents include, but are not limited
to, kinase inhibitors, such as EGFR inhibitors (e.g., erlotinib,
gefitinib), Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors
(e.g., sunitinib), ALK inhibitors (e.g., crizotinib) standard
chemotherapy agents such as alkylating agents, antimetabolites,
anti-tumor antibiotics, topoisomerase inhibitors, platinum drugs,
mitotic inhibitors, antibodies, hormone therapies, or
corticosteroids. For pain indications, suitable combination agents
include anti-inflammatories such as NSAIDs. The pharmaceutical
compositions of the invention may additionally comprise one or more
of such active agents, and methods of treatment may additionally
comprise administering an effective amount of one or more of such
active agents.
Chemical Synthesis
[0281] Exemplary chemical entities useful in methods of the
description will now be described by reference to illustrative
synthetic schemes for their general preparation below and the
specific examples that follow. Artisans will recognize that, to
obtain the various compounds herein, starting materials may be
suitably selected so that the ultimately desired substituents will
be carried through the reaction scheme with or without protection
as appropriate to yield the desired product. Alternatively, it may
be necessary or desirable to employ, in the place of the ultimately
desired substituent, a suitable group that may be carried through
the reaction scheme and replaced as appropriate with the desired
substituent. Furthermore, one of skill in the art will recognize
that the transformations shown in the schemes below may be
performed in any order that is compatible with the functionality of
the particular pendant groups.
[0282] Abbreviations: The examples described herein use materials,
including but not limited to, those described by the following
abbreviations known to those skilled in the art:
TABLE-US-00002 g grams eq equivalents mmol millimoles mL
milliliters EtOAc ethyl acetate MHz megahertz ppm parts per million
.delta. chemical shift s singlet d doublet t triplet q quartet quin
quintet br broad m multiplet Hz hertz THF tetrahydrofuran .degree.
C. degrees Celsius PE petroleum ether EA ethyl acetate R.sub.f
retardation factor N normal J coupling constant DMSO-d.sub.6
deuterated dimethyl sulfoxide n-BuOH n-butanol DIEA
n,n-diisopropylethylamine TMSCl trimethylsilyl chloride min minutes
hr hours Me methyl Et ethyl i-Pr isopropyl TLC thin layer
chromatography M molar Compd# compound number MS mass spectrum m/z
mass-to-charge ratio Ms methanesulfonyl FDPP pentafluorophenyl
diphenylphosphinate Boc tert-butyloxycarbonyl TFA trifluoroacetic
acid Tos toluenesulfonyl DMAP 4-(dimethylamino)pyridine .mu.M
micromolar ATP adenosine triphosphate IC.sub.50 half maximal
inhibitory concentration U/mL units of activity per milliliter
KHMDS potassium bis(trimethylsilyl)amide DIAD diisopropyl
azodicarboxylate MeTHF 2-methyltetrahydrofuran MOM methoxymethyl
DCM dichloromethane DMF N,N-dimethylformamide DPPA diphenyl
phosphoryl azide DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DIPEA
N,N-iisopropylethylamine TBAF Tetrabutylammonium Fluoride TEA
Triethylamine TBS Tert-butyldimethylsilyl
[0283] General Method A.
Preparation of tert-butyl
{(2S)-2-[4-fluoro-2-({[(1R,2S)-2-hydroxycyclopentyl]amino}methyl)phenoxy]-
propyl}carbamate (A-1)
##STR00088##
[0285] Step 1. To an azeotrope dried mixture of A-1-1 (0.9615 g,
5.65 mmol) and A-1-1A (1.19 g, 6.78 mmol) in DCM (3.62 mL) was
added PPh.sub.3 (2.22 g, 8.48 mmol) The mixture was stirred until
everything dissolved. DIAD (1.83 g, 9.04 mmol, 1.78 mL) was added
very slowly with mixing at 0.degree. C. The reaction was warmed to
25.degree. C. and stirred for 16 hr. DCM (5 mL) and 2M NaOH
solution (20 mL) were added and stirred vigorously for 4 hours. The
mixture was extracted with DCM (3.times.15 mL), dried with
Na.sub.2SO.sub.4 and concentrated under reduced pressure. Flash
chromatography (ISCO system, silica 12 g, 0-30% ethyl acetate in
hexane) provided A-1-2 (1.35 g, 73%).
[0286] Step 2. To a solution of A-1-2 (1.35 g, 4.13 mmol) in THF
(8.27 mL) at 0.degree. C. was added lithium borohydride (720.51 mg,
33.08 mmol) in small batches and the mixture was stirred for 1 hr
and was removed from the cold bath. The mixture stirred at ambient
temperature for 20 hr, then diluted with water (5 mL) and extracted
with ethyl acetate (3.times.5 mL). The combined organic phase was
washed with brine and dried over sodium sulfate. Flash column
chromatography (ISCO, silica, 24 g, ethyl acetate in hexanes)
afforded A-1-3 (1.08 g, 3.60 mmol, 87.09% yield).
[0287] Step 3. DMSO (422.82 mg, 5.41 mmol, 384.38 uL) in DCM (6 mL)
was added dropwise at -78.degree. C. to oxalyl chloride (686.85 mg,
5.41 mmol, 464.09 uL) in DCM (6 mL). The mixture was stirred for 20
minutes and A-1-3 (1.08 g, 3.61 mmol) in DCM (6 mL) was added
dropwise at -78.degree. C. and stirred for 20 minutes followed by
addition of TEA (1.83 g, 18.04 mmol, 2.51 mL). The mixture was
stirred as temperature increased to ambient temperature over 18 h.
The reaction was quenched with water (10 mL) and the layers were
separated. The aqueous layer was extracted twice more with DCM
(2.times.10 mL). The combined organic layer was washed with brine
and dried over sodium sulfate. Flash chromatography (ISCO, 24 g
Silica Gold, 0-30% ethyl acetate in hexanes) afforded A-1-4 (460.2
mg, 1.55 mmol, 42.90% yield).
[0288] Step 4. A solution of (1S,2R)-2-aminocyclopentanol HCl salt
(69 mg, 504 .mu.mol), Hunig's Base (196 mg, 0.26 mL, 1.5 mmol) and
A-1-4 (150.00 mg, 504 .mu.mol) in dry MeOH (2.50 mL) was heated to
65.degree. C. for 1 hr. The reaction was cooled to room temperature
and NaBH.sub.4 (38 mg, 1.0 mmol) was added. The mixture was stirred
for 2 hr then quenched with water (3 mL) and stirred for 5 min. The
mixture was extracted with DCM (3.times.5 mL), dried with
Na.sub.2SO.sub.4 and concentrated under reduced pressure. Flash
chromatography (ISCO system, silica (12 g), 25-50% ethyl acetate in
hexane) provided A-1 (125.3 mg, 327 .mu.mol, 64.9% yield).
[0289] Compound A-2 was prepared according to General Method A
using (1R,2R)-2-aminocyclopentanol in step 4.
[0290] General Method B.
Preparation of tert-butyl
{(2S)-2-[2,4-difluoro-6-({[(1R,2S)-2-hydroxycyclopentyl]amino}methyl)phen-
oxy]propyl}carbamate (A-3)
##STR00089##
[0292] Step 1. Added K.sub.2CO.sub.3 (330.00 mg, 2.39 mmol) to
A-3-1 (151 mg, 955.08 .mu.mol) and A-3-1A (283.27 mg, 1.19 mmol) in
DMF (4.78 mL) and heated to 50.degree. C. with stirring for 1 hr.
The mixture was cooled and diluted with DCM (3 mL), filtered
through a syringe filter and concentrated under reduced pressure.
Flash chromatography (ISCO system, silica (12 g), 0-30% ethyl
acetate in hexane) provide A-3-2 (301 mg, 954 .mu.mol, 99%
yield).
[0293] Step 4. A solution of (1S,2R)-2-aminocyclopentanol HCl salt
(104 mg, 0.76 .mu.mol) and A-3-2 (200 mg, 634 .mu.mol) in dry MeOH
(3.17 mL) was heated to 65.degree. C. for 1 hour. The reaction was
cooled to room temperature and NaBH.sub.4 (72 mg, 1.9 mmol) was
added. The mixture was stirred for 2 hours then quenched with water
(5 mL) and stirred for 5 min. The mixture was extracted with DCM
(3.times.15 mL), dried with Na.sub.2SO.sub.4 and concentrated under
reduced pressure. Flash chromatography (ISCO system, silica (12 g),
0-20% methanol in dichloromethane) provided A-3 (108 mg, 270
.mu.mol, 42% yield).
[0294] Compound A-4 was prepared according to General Method A
using (3R,4R)-4-aminotetrahydrofuran-3-ol in step 4.
[0295] Compound A-5 was prepared according to General Method A
using 5-Fluoro-2-methoxynicotinaldehyde in step 4.
[0296] Compound A-6 was prepared according to General Method A
using rac cis-tert-butyl-3-amino-4-hydroxypyrrolidine-1-carboxylate
and 5-Fluoro-2-methoxynicotinaldehyde.
TABLE-US-00003 MS [M + H] Compd# Structure m/z A-1 ##STR00090##
383.2 A-2 ##STR00091## 383.2 A-3 ##STR00092## 401.2 A-4
##STR00093## 385.2 A-5 ##STR00094## 241.1 A-6 ##STR00095##
342.1
[0297] General Method C.
Preparation of ethyl
6-bromo-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (B-1)
##STR00096##
[0299] Step 1. To a solution of B-1-1 (10.00 g, 47.80 mmol, 1.00
eq.) in acetic acid (100.00 mL) was added bromine (7.64 g, 47.80
mmol, 2.46 mL, 1.00 eq.). The mixture was stirred at 180.degree. C.
for 6 hr. TLC (petroleum ether/ethyl acetate=1/1) showed the
starting material was consumed completely and one new spot was
found. The mixture was quenched by water (30 mL). The mixture was
filtered and the cake was concentrated to give B-1-2 (10.00 g,
34.71 mmol, 72.62% yield) as a white solid: .sup.1H NMR (400 MHz,
DMSO-d6) .delta.: 12.34 (br. s., 1H), 9.25 (s, 1H), 8.15 (s, 1H),
4.28 (q, J=7.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).
[0300] Step 2. To a solution of B-1-2 (6.00 g, 20.97 mmol, 1.00
eq.) in phosphorus oxychloride (60 mL). The mixture was stirred at
120.degree. C. for 16 hr. TLC (petroleum ether/ethyl acetate=3/1)
indicated the starting material was consumed completely and one new
spot was found. The reaction mixture was filtered and concentrated
under reduced pressure to give a residue. The residue was purified
by column chromatography (SiO.sub.2, petroleum ether/ethyl
acetate=10/1 to 1/1) to give B-1 (2.50 g, 8.21 mmol, 39.15% yield)
as a white solid; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 8.94
(s, 1H), 8.54 (s, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz,
3H).
[0301] General Method D.
Preparation of
(3aR,11S,20aS)-7-fluoro-11-methyl-2,3,3a,12,13,20a-hexahydro-1H,5H-17,19--
(metheno)cyclopenta[5,6][1,4]oxazino[3,4-i]pyrazolo[4,3-f][1,4,8,10]benzox-
atriazacyclotridecin-14(11H)-one (1)
##STR00097##
[0303] Step 1. To a solution of B-1 (325 mg, 1.07 mmol) and A-1
(408 mg, 1.07 mmol) in n-BuOH (5.3 mL) was added Hunig's base (689
mg, 5.3 mmol, 929 .mu.L). The mixture was heated to 90.degree. C.
for 15 hr. The reaction was cooled and concentrated under reduced
pressure. Flash chromatography (ISCO system, silica (12 g), 10-50%
ethyl acetate in hexane) provided 1-1 (197.7 mg, 303 .mu.mol, 28%
yield).
[0304] Step 2. To a solution of 1-1 (36.6 mg, 48.5 .mu.mol) in DMF
(3 mL) was added KOt-Pent (1.7 M, 86 .mu.L) in toluene. The
reaction stirred at room temperature for 1.5 hours. The reaction
was cooled to -20.degree. C. and quenched with saturated NH.sub.4Cl
sol. (5 mL) then extracted with DCM (3.times.10 mL). Combined
extracts were dried with Na.sub.2SO.sub.4 and concentrated under
reduced pressure. Flash chromatography (ISCO system, silica (12 g),
10-35% ethyl acetate in hexane) provided 1-2 (12.8 mg, 22 .mu.mol,
46% yield).
[0305] Step 3. To a solution of 1-2 (12.8 mg, 22 .mu.mol) in MeOH
(3 mL) and THF (1 mL) at ambient temperature was added aqueous LiOH
solution (2.0 M, 1.0 mL). The mixture was heated at 60.degree. C.
for 17 hr, cooled to -20.degree. C. then quenched with aqueous HCl
solution (2.0 M) to acidic. The mixture was extracted with DCM
(3.times.5 mL), dried with Na.sub.2SO.sub.4, concentrated under
reduced pressure, and dried under high vacuum. The crude material
was dissolved in DCM (4 mL) followed by addition of HCl in
1,4-dioxane (4 M, 3 mL). The mixture was stirred at ambient
temperature for 1.5 hr, concentrated under reduced pressure, and
dried under high vacuum. The crude material was dissolved in in DMF
(2.0 mL) and DCM (4.0 mL) and Hunig's base (185 mg, 1.4 mmol, 250
.mu.L) then FDPP (34.5 mg, 89 .mu.mol) was added in one portion.
The reaction was stirred for 1.5 hours then quenched with 2 M
Na.sub.2CO.sub.3 solution (5 mL). The mixture was stirred for 5 min
then extracted with DCM (4.times.10 mL). Combined extracts were
dried with Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Flash chromatography (ISCO system, silica (12 g), 0-5%
methanol in dichloromethane) provided 1 (8.13 mg, 19 .mu.mol, 85%
yield).
[0306] Compounds 2 through 4 were prepared according to General
Method D using A-2 through A-4 in step 1 respectively.
[0307] General Method E.
Preparation of
(3aR,11S,20aS)-7-fluoro-11-methyl-2,3,3a,12,13,20a-hexahydro-1H,5H-17,19--
(metheno)cyclopenta[5,6][1,4]oxazino[3,4-i]pyrazolo[4,3-f]pyrido[3,2-l][1,-
4,8,10]oxatriazacyclotridecin-14(11H)-one (5)
##STR00098##
[0309] Step 1. To a solution of B-1 (454 mg, 1.49 mmol) and A-5
(358 mg, 1.49 mmol) in t-BuOH (5.0 mL) was added Hunig's base (963
mg, 7.45 mmol, 1.30 mL). The mixture was heated to 105.degree. C.
for 17 hr. The reaction was cooled and concentrated under reduced
pressure. Flash chromatography (ISCO system, silica (12 g), 10-40%
ethyl acetate in hexane) provided 5-1 (292 mg, 38% yield).
[0310] Step 2. To a solution of 5-1 (18.8 mg, 37 .mu.mol) in DMF (3
mL) was added KOt-Pent (1.7 M, 65 .mu.L) in toluene. The reaction
stirred at room temperature for 20 hours. The reaction was cooled
to -20.degree. C. and quenched with saturated NH.sub.4Cl sol. (5
mL) then extracted with DCM (3.times.10 mL). Combined extracts were
dried with Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Flash chromatography (ISCO system, silica (12 g), 0-5%
methanol in dichloromethane) provided 5-2 (6.2 mg, 39% yield).
[0311] Step 3. To a solution of 5-2 (6.2 mg, 14.5 .mu.mol) in EtOH
(4 mL) was added aqueous HCl solution (4.0 M, 3.0 mL) in
1,4-dioxane. The mixture was heated at 70.degree. C. for 6 hours.
The mixture was cooled, concentrated under reduced pressure, and
dried under high vacuum to provide crude 5-3. Compound was used as
is.
[0312] Step 4. Added K.sub.2CO.sub.3 (14.0 mg, 101 .mu.mol) to 5-3
(6.2 mg, 14.5 .mu.mol) and A-3-1A (17 mg, 73 .mu.mol) in DMF (250
.mu.L) and stirred for 2 hours. The mixture was cooled and quenched
with water (5 mL) then extracted with DCM (3.times.10 mL). Combined
extracts were dried with Na.sub.2SO.sub.4 and concentrated under
reduced pressure. Flash chromatography (ISCO system, silica (12 g),
20-100% ethyl acetate in hexane) provide 5-4 (6.1 mg, 73%
yield).
[0313] Step 5. To a solution of 5-4 (6.1 mg, 10.7 .mu.mol) in MeOH
(3 mL) and THF (1 mL) at ambient temperature was added aqueous LiOH
solution (2.0 M, 1.0 mL). The mixture was heated at 60.degree. C.
for 16 hr, cooled to -20.degree. C. then quenched with aqueous HCl
solution (2.0 M) to acidic. The mixture was extracted with DCM
(3.times.5 mL), dried with Na.sub.2SO.sub.4, concentrated under
reduced pressure, and dried under high vacuum. The crude material
was dissolved in DCM (4 mL) followed by addition of HCl in
1,4-dioxane (4 M, 3 mL). The mixture was stirred at ambient
temperature for 2 hours, concentrated under reduced pressure, and
dried under high vacuum. The crude material was dissolved in in DMF
(2.0 mL) and DCM (4.0 mL) and Hunig's base (185 mg, 1.4 mmol, 250
.mu.L) then FDPP (34.5 mg, 89 .mu.mol) was added in one portion.
The reaction was stirred for 1 hour then quenched with 2 M
Na.sub.2CO.sub.3 solution (5 mL). The mixture was stirred for 5 min
then extracted with DCM (4.times.10 mL). Combined extracts were
dried with Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Flash chromatography (ISCO system, silica (12 g), 0-5%
methanol in dichloromethane) provided 5 (3.21 mg, 71% yield).
[0314] Compound 6 was prepared according to General Method E using
(R)-3-Boc-4-methyl-2, 2-dioxo-[1,2,3]oxathiazolidine in step 4.
[0315] General Method F.
Preparation of ethyl
(5aR,8aS)-5,5a,6,7,8,8a-hexahydrocyclopenta[b]pyrazolo
[1',5':1,2]pyrimido[4,5-e][1,4]oxazine-3-carboxylate (C-1)
##STR00099##
[0317] Step 1. To a solution of C-1-1 (5.0 g, 28.1 mmol, 1 eq.) and
C-1-2 (6.1 g, 39.3 mmol, 1.4 eq.) in EtOH (56 mL) at 90.degree. C.
was added NaOEt (2.68 M, 26.2 mL, 2.5 eq.) and was stirred for 6
hours. The reaction mixture cooled and diluted with Toluene (60 mL)
and concentrated to dryness under reduced pressure. The material
was resuspended in Toluene (60 mL) and again concentrated to
dryness and placed on a high vac overnight to provide crude C-1-3.
Crude material was used as is in next step.
[0318] Step 2. The crude C-1-3 from step 1 was suspended in
POCl.sub.3 (99 g, 60 mL, 646 mmol, 23.00 eq.) and heated to
100.degree. C. for 24 hours. The reaction was cooled to room
temperature and concentrated to dryness under reduced pressure. The
crude material was suspended in DCM (100 mL) and water (100 mL) was
added. The mixture was stirred for 30 min then extracted with DCM
(3.times.100 mL). The combined organic extracts were washed by
brine (100 mL), dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure. Purification through a Silica
plug (60 g Si), eluted with DCM (.about.1.5 L) gave C-1-4 (5.68 g,
72% yield, purity=86% by LC/MS) as a yellow solid.
[0319] Step 3. To a solution of C-1-4 (5.68 g, 20.4 mmol) and
NH.sub.4Cl (5.46 g, 102 mmol) in THF (68 mL), EtOH (204 mL) and
water (136 mL) at 0.degree. C. was added Zn powder (5.34 g, 81.7
mmol). The mixture was stirred at 0.degree. C. for 3 hours. The
reaction mixture was filtered through a celite pad and the celite
pad was rinsed with DCM (100 mL). The filtrate was concentrated to
dryness under reduced pressure then resuspended in DCM (500 mL)
dried with Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Purification using a silica plug (50 g Si) and elution
with DCM provided C-1-5 (3.17 g, 63.8% yield) as a white solid.
[0320] Step 4. To a solution of C-1-5 (1.74 g, 7.1 mmol) and the
HCl salt of (1S,2R)-2-aminocyclopentanol (1.08 g, 7.8 mmol) in EtOH
(14 mL) was added DIEA (4.6 g, 6.2 mL 35.6 mmol). The mixture was
heated to 80.degree. C. for 1 hour. The reaction cooled and
concentrated under reduced pressure. Flash chromatography (ISCO
system, silica (40 g), 20-80% ethyl acetate in hexane) provided
C-1-6 (2.13 g, 97% yield) as a white solid.
[0321] Step 5. To a solution of C-1-6 (1.0 g, 3.24 mmol) in DMSO
(162 mL) was added Cs.sub.2CO.sub.3 (9.51 g, 29 mmol). The mixture
was heated to 100.degree. C. and stirred for 91 hours. The reaction
mixture was cooled and quenched with 30% brine solution (700 mL)
then extracted with ethyl acetate (4.times.200 mL). Combined
extracts were washed with 15% brine solution (2.times.250 mL).
Brine solutions were back extracted with ethyl acetate (1.times.250
mL). Organic extracts were combined and dried with brine (250 mL),
Na.sub.2SO.sub.4 and concentrated under reduced pressure to provide
C-1 (803 mg, 86% yield, 97% purity by LC/MS) as a light-yellow
solid.
[0322] Compounds C-2, C-3, and C-4 were prepared according to
General Method F using rac cis-2-aminocyclobutanol,
(1S,2R)-2-aminocyclohexanol, and rac cis-4-aminooxolan-3-ol,
respectively in step 4.
TABLE-US-00004 MS [M + H] Compd# Structure m/z C-1 ##STR00100##
289.0 C-2 ##STR00101## 275.0 C-3 ##STR00102## 303.0 C-4
##STR00103## 291.1
[0323] General Method G.
Preparation of tert-butyl
{(2R)-1-[2-(chloromethyl)-4,6-difluorophenoxy]propan-2-yl}carbamate
(D-1)
##STR00104##
[0325] Step 1. To a solution of D-1-1 (200 mg, 1.27 mmol) and
D-1-1A (315 mg, 1.33 mmol) in DMF (6.3 mL) was added
K.sub.2CO.sub.3 (437 mg, 3.2 mmol) The reaction was stirred for 2
hours then quenched with citric acid solution (1 M in H.sub.2O, 6
mL) was added and the mixture was vigorously stirred for 30
minutes. The mixture was extracted with DCM (3.times.10 mL) and
combined organic extracts were collected and dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
and high vacuum to afforded desired product D-1-2 (theoretical
yield 399 mg). Compound was used as is.
[0326] Step 2. To a solution of D-1-2 (399 mg (theoretical), 1.27
mmol) in dry THF (15 mL) was added LiBH.sub.4 (193 mg, 8.86 mmol).
The mixture was stirred for 20 hours then quenched with water (25
mL) and stirred for 5 min. The mixture was extracted with DCM
(3.times.15 mL), dried with Na.sub.2SO.sub.4 and concentrated under
reduced pressure. Flash chromatography (ISCO system, silica (24 g),
0-50% ethyl acetate in hexane) provided D-1-3 (33.2 mg, 8%
yield).
[0327] Step 3. To a solution of D-1-3 (33.2 mg, 105 .mu.mol) and
DIPEA (67.6 mg, 91 .mu.L, 523 .mu.mol) in DCM (525 .mu.L) at
0.degree. C. was added MsCl (15 mg, 10 .mu.L 131 .mu.mol) dropwise.
The mixture stirred at 0.degree. C. for 1 hour. The reaction was
quenched with water (3 mL) and 2M HCl (100 .mu.L) then extracted
with DCM (3.times.5 mL). The organic phases were combined, dried
over Na.sub.2SO.sub.4, and concentrated under reduced pressure.
Flash chromatography (ISCO system, silica (12 g), 0-50% ethyl
acetate in hexane) provided a mixture of D-1 and D-1A (40.2 mg, 91%
yield).
[0328] General Method H.
Preparation of
(S)-(2-((1-((tert-butoxycarbonyl)amino)propan-2-yl)oxy)-5-fluoropyridin-3-
-yl)methyl methanesulfonate (D-2)
##STR00105##
[0330] Step 1. D-2-1 (7 g, 45.12 mmol) and pyridine hydrochloride
(20.86 g, 180.5 mmol) were mixed in a round bottom flask and heated
up to 145.degree. C. and the molten mixture was stirred at
145.degree. C. for 30 min then cooled down. The mixture was diluted
with H.sub.2O (200 mL) and ethyl acetate (200 mL), partitioned and
the aqueous layer was extracted with EA (5.times.100 mL), organic
phases were combined and dried over Na.sub.2SO.sub.4, the solution
was then concentrated under reduced pressure to afford desired
product D-2-1 (5.19 g, 36.78 mmol, 81.51% yield) as yellow
solid.
[0331] Step 2. To an ice-bathed mixture of compound D-2-1 (2.37 mg,
16.79 mmol) and Cs.sub.2CO.sub.3 (21.88 g, 67.15 mmol in NMP (33.57
mL) was added compound A-3-1A (4 g, 16.79 mmol), the reaction was
stirred at 0.degree. C. for 2 hours. The reaction was diluted with
dichloromethane (200 mL) and H.sub.2O (100 mL). Citric acid
solution (1 M in H.sub.2O, 100 mL) was added and the mixture was
vigorously stirred for 10 minutes, layers were separated, organic
layer was collected and dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. Purification by flash
chromatography (ISCO system, silica (80 g), 0-30% ethyl acetate in
hexanes) afforded desired product D-2-2 (4.2 g, 14.06 mmol, 83.79%
yield) as white solid.
[0332] Step 3. To an ice-bathed solution of compound D-2-2 (4.2 g,
14.06 mmol) in MeOH (46.88 mL) was added NaBH.sub.4 (798.17 mg,
21.10 mmol). The reaction was stirred under 0.degree. C. for 1
hour. The reaction was quenched with H.sub.2O (100 mL) and was
extracted with dichloromethane (3.times.100 mL). The organic phases
were combined and dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. Purification by flash
chromatography (ISCO system, silica (80 g), 0-50% ethyl acetate in
hexanes) afforded desired product D-2-3 (3.46 g, 11.53 mmol, 81.96%
yield) as colorless oil.
[0333] Step 4. To a solution of D-2-3 (2.41 g, 8.02 mmol) and the
DIPEA (4.15 g, 5.6 mL, 32.1 mmol) in DCM (14 mL) at 0.degree. C.
was added MsCl (1.10 g, 0.74 mL 9.62 mmol) dropwise. The mixture
stirred at 0.degree. C. for 2 hours. The was quenched with 1% HCl
solution (100 mL) and extracted with DCM (3.times.100 mL). The
organic phases were combined, dried over Na.sub.2SO.sub.4, and
concentrated under reduced pressure. Flash chromatography (ISCO
system, silica (80 g), 0-40% ethyl acetate in hexane) provided D-2
(2.0 g, 66% yield) as a white solid and D-2A (627 mg, 24% yield) as
an oil.
[0334] Compound D-3 was prepared according to General Method H
using (R)-3-boc-4-methyl-2,2-dioxo-[1,2,3]oxathiazolidine in step
2.
TABLE-US-00005 MS [M + Na] Compd# Structure m/z D-1 ##STR00106##
418.1 D-2 ##STR00107## 401.1 D-3 ##STR00108## 401.1
[0335] General Method I.
Preparation of
(3aR,12R,20aS)-7,9-difluoro-12-methyl-2,3,3a,12,13,20a-hexahydro-1H,5H-17-
,19-(metheno)cyclopenta[5,6][1,4]oxazino[3,4-i]pyrazolo[4,3-f][1,4,8,10]be-
nzoxatriazacyclotridecin-14(11H)-one (7)
##STR00109##
[0337] Step 1. To a solution of C-1 (30 mg, 104 .mu.mol) and D-1
(41 mg, 104 .mu.mol) in DMF (1 mL) was added Cs.sub.2CO.sub.3 (102
mg, 312 .mu.mol). The reaction was stirred at room temperature for
4 hours. The reaction was cooled, diluted with DCM (3 mL), filtered
through a syringe filter and concentrated under reduced pressure.
Flash chromatography (ISCO system, silica (12 g), 0-50% ethyl
acetate in hexane) provided 7-1 (61 mg, 100% yield).
[0338] Step 2. Compound 7-1 was converted to 7 following the
procedure used in General Method E.
[0339] Compounds 8 and 9 were prepared according to General Method
I using starting materials C-2 and D-2 in step 1 and separating the
stereoisomers after the last step.
[0340] Compounds 10 and 11 were prepared according to General
Method I using starting materials C-2 and D-3 in step 1 and
separating the stereoisomers after the last step.
[0341] Compound 12 was prepared according to General Method I using
starting materials C-3 and D-2 in step 1.
[0342] Compound 13 was prepared according to General Method I using
starting materials C-3 and D-3 in step 1.
[0343] General Method J.
Preparation of
(3aR,12R,20aS)-12-cyclopropyl-7-fluoro-2,3,3a,12,13,20a-hexahydro-1H,5H-1-
7,19-(metheno)cyclopenta[5,6][1,4]oxazino[3,4-i]pyrazolo[4,3-f]pyrido[3,2--
l][1,4,8,10]oxatriazacyclotridecin-14(11H)-one (14)
##STR00110##
[0345] Step 1. To a solution of 14-1 (1.0 g, 8.69 mmol) in dry MeOH
(87 mL) was added HCl (4.0 M, 4.3 mL, 2.0 eq.) in dioxane. The
mixture was heated to 70.degree. C. and stirred for 40 hours. The
reaction mixture cooled and concentrated to dryness under reduced
pressure to provide crude 14-2. The material was used as is in next
step.
[0346] Step 2. To a solution of crude 14-2 from step 1 in THF (60
mL) was added Boc.sub.2O (2.08 g, 9.54 mmol) and NaHCO.sub.3
solution (1 M, 34.69 mL). The reaction was stirred for 4 hours then
diluted with water (50 mL) and then extracted with ethyl acetate
(3.times.50 mL). The combined organic extracts were washed by brine
(50 mL), dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure. Flash chromatography (ISCO
system, silica (40 g), 0-50% ethyl acetate in hexane) provided 14-3
(1.66 g, 83% yield).
[0347] Step 3. To a solution of 14-3 (1.66 g, 7.24 mmol) in THF (36
mL) at 0.degree. C. was added LiBH.sub.4 (789 mg, 36 mmol). The
mixture was slowly warmed to room temperature and stirred for 20
hours. The reaction mixture was quenched by addition of water (20
mL) and aqueous saturated NH.sub.4Cl (25 mL) then extracted with
ethyl acetate (3.times.50 mL). Combined extracts were dried with
brine (50 mL), Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Flash chromatography (ISCO system, silica (40 g), 10-40%
ethyl acetate in hexane) provide 14-4 (1.23 g, 84% yield).
[0348] Step 4. To a solution of Imidazole (1.0 g, 14.9 mmol) in DCM
(16 mL) at -5.degree. C. was added SOCl.sub.2 (532 mg, 4.47 mmol,
324 .mu.L) in DCM (5 mL) dropwise. The mixture was stirred at
-5.degree. C. for 1 hour. The mixture was cooled to -10.degree. C.
and 14-4 (0.5 g, 2.48 mmol) in DCM (4 mL) was added dropwise. The
mixture was slowly warmed to 10.degree. C. and stirred at this
temperature for 2 hr. The reaction was quenched with water (10 mL)
and stirred at 10.degree. C. for 10 min. The organic layer was
removed and washed with 10% citric acid solution (10 mL) then dried
with brine (5 mL) and Na.sub.2SO.sub.4 and concentrated under
reduced pressure. Flash chromatography (ISCO system, silica (24 g),
0-20% ethyl acetate in hexane) provide 14-5 (294 mg, 48%
yield).
[0349] Step 5. To a solution of 14-5 (294 mg, 1.19 mmol) in DCM
(5.66 mL) and NaIO4 (610.25 mg, 2.85 mmol) in H2O (5.66 mL) at
0.degree. C. was added RuCl.sub.3*3H.sub.2O (6.2 mg, 24 .mu.mol).
The reaction was warmed to room temperature and stirred for 1 hour.
The reaction was quenched with water (15 mL) then extracted with
DCM (3.times.15 mL). Combined extracts were dried with brine (5
mL), Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Flash chromatography (ISCO system, silica (12 g), 0-30% ethyl
acetate in hexane) provide 14-6 (308 mg, 98% yield).
[0350] Step 6. To a solution of 5-3 (40 mg, 97 .mu.mol) and 14-6
(32 mg, 121 .mu.mol) in DMF (484 .mu.L) was added CS2CO3 (95 mg,
290 .mu.mol). The reaction mixture was stirred for 1 hour then
diluted with DCM (5 mL) and filtered through syringe filter then
stirred with 20% citric acid solution (10 mL) for 30 min. The
mixture was extracted with DCM (3.times.15 mL) and combined
extracts dried with Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Flash chromatography (ISCO system, silica (12 g), 10-50%
ethyl acetate in hexane) provide 14-7 (45.6 mg, 79% yield).
[0351] Step 7. Compound 14-7 was converted to 14 following the
procedure used in General Method E.
[0352] General Method K.
Preparation of
(3aR,11S,21aS)-7-fluoro-11-methyl-2,3,3a,11,12,13,14,21a-octahydro-1H,5H,-
15H-18,20-(metheno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido-
[2,3-b][1,5,7,11]oxatriazacyclotetradecin-15-one (15)
##STR00111##
[0354] Step 1. To a solution of 5-3 (50 mg, 121 .mu.mol), 15-1-1A
(27.5 mg, 145 .mu.mol) and PPh.sub.3 (41 mg, 157 .mu.mol) in DCM
(194 .mu.L) at 0.degree. C. was added DIAD (41 mg, 157 .mu.mol).
The mixture was warmed to room temperature and stirred for 16
hours. The reaction cooled and diluted with DCM. The solution was
filtered and the filtrate was concentrated under reduced pressure.
Flash column chromatography (ISCO, silica, a 12 g, ethyl acetate in
hexanes) to afford 15-1 (58.8 mg, 83% yield)
[0355] Step 2. Compound 15-1 was converted to 15 following the
procedure used in General Method E.
[0356] Compounds 16 and 17 were prepared according to General
Method K.
[0357] Compound 18 was prepared according to General Method J.
[0358] General Method L.
Preparation of
(3aR,21aS)-7-fluoro-2,3,3a,11,12,13,14,21a-octahydro-1H,5H,15H-18,20-(met-
heno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido[2,3-b][1,5,7,-
11]oxatriazacyclotetradecin-15-one (19)
##STR00112##
[0360] Step 1. To a solution of 5-3 (40 mg, 97 .mu.mol) and 19-1-1A
(23 mg, 116 .mu.mol) in DMF (300 uL) was added K.sub.2CO.sub.3 (27
mg, 194 .mu.mol). The mixture was mixture was stirred at room
temperature for 16 hr. The reaction cooled and diluted with DCM (5
mL). The solution was filtered and the filtrate was concentrated
under reduced pressure. The crude was purified by flash column
chromatography (ISCO, silica, 12 g, ethyl acetate in hexanes) to
afford 15 (18.9 mg, 34% yield).
[0361] Step 2. Compound 19-1 was converted to 19 following the
procedure used in General Method E.
[0362] Compound 20 was prepared according to General Method K.
[0363] Compound 21 and 22 were prepared according to General Method
J.
[0364] Compound 23 and 24 were prepared according to General Method
K.
[0365] Compound 25 and 26 were prepared according to General Method
J.
[0366] Compound 27, 28, and 29 were prepared according to General
Method K.
[0367] Compound 30 and 31 were prepared according to General Method
I using starting materials D-2A and C-4 in step 1 and separating
the stereoisomers after the last step by flash column
chromatography (ISCO, reverse phase C-18, 50 g, acetonitrile in
water with 0.035% TFA).
[0368] General Method M.
Preparation of
(3aR,12S,21aS)-7-fluoro-12-hydroxy-2,3,3a,11,12,13,14,21a-octahydro-1H,5H-
,15H-18,20-(metheno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrid-
o[2,3-b][1,5,7,11]oxatriazacyclotetradecin-15-one (32)
##STR00113##
[0370] Step 1. To a solution of 32-1 (3.1 g, 34.03 mmol) and Boc
anhydride (7.43 g, 34.03 mmol) in MeOH (68.05 mL) was added TEA
(6.89 g, 68.05 mmol, 9.48 mL). The mixture was stirred at room
temperature for 16 hr. The reaction was concentrated under reduced
pressure and purified by flash column chromatography (ISCO, silica,
40 g, methanol in dichloromethane) to afford 32-2 (6.36 g, 33.26
mmol, 97.75% yield).
[0371] Step 2. 32-2 (6.36 g, 33.26 mmol) and imidazole (4.53 g,
66.52 mmol) were dissolved in THF (110.86 mL) and TBS chloride
(6.02 g, 39.91 mmol) was added. The mixture was stirred for 2 hr
then diluted with water (200 mL) and extracted with DCM
(3.times.200 mL). The combined organic phase was washed with brine
(200 mL) and dried over Na.sub.2SO.sub.4. The solution was filtered
and the filtrate was concentrated under reduced pressure. The crude
was purified by flash chromatography (ISCO system, silica, 80 g,
0-40% ethyl acetate in hexanes) to afford 32-3 (8.75 g, 28.64 mmol,
86.12% yield).
[0372] Step 3. To a solution of 32-3 (8.75 g, 28.64 mmol) and DIEA
(11.11 g, 85.93 mmol, 14.97 mL) in DCM (95.48 mL) at 0.degree. C.
was added MOM chloride (3.46 g, 42.96 mmol, 3.26 mL) slowly. The
mixture was stirred for 16 hr. warming to ambient temperature. The
reaction was quenched with water (100 mL) and extracted with DCM
(3.times.100 mL). The combined extracts were dried over
Na.sub.2SO.sub.4. The crude was purified by flash column
chromatography (ISCO, silica, 80 g, 0-30% ethyl acetate in hexanes)
to afford 32-4 (7.44 g, 21.29 mmol, 74.31% yield).
[0373] Step 4. To a solution of 32-4 (7.44 g, 21.29 mmol) in THF
(106.43 mL) was added TBAF Monohydrate (11.90 g, 42.57 mmol). The
mixture was stirred for 1 hr. then quenched with saturated aqueous
NH.sub.4Cl solution (10 mL) and diluted with DCM (100 mL). The
mixture was dried over Na.sub.2SO.sub.4 and filtered. The filtrate
was concentrated under reduced pressure and the crude was purified
by flash column chromatography (ISCO, silica, 80 g, ethyl acetate
in hexanes) to afford 32-5 (4.67 g, 19.85 mmol, 93.25% yield).
[0374] Compound 32 was prepared following General Method J from
32-5 in step 4 and 5-3 in step 6.
[0375] General Procedure N.
Preparation of
(3aR,21aS)-7-fluoro-12,12-dihydroxy-2,3,3a,11,12,13,14,21a-octahydro-1H,5-
H,15H-18,20-(metheno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyri-
do[2,3-b][1,5,7,11]oxatriazacyclotetradecin-15-one (33)
##STR00114##
[0377] To a solution of 32 (13.8 mg, 31.33 umol) in DCM (626.66 uL)
was added Dess-Martin Periodinane (26.58 mg, 62.67 umol). The
mixture was stirred at room temperature for 2 hr and quenched with
saturated NaHCO.sub.3 solution (5 mL). The mixture was extracted
with DCM (3.times.5 mL) and the organic layers dried over
Na.sub.2SO.sub.4. The salts were filtered and the filtrate
concentrated under reduced pressure. The crude was purified by
flash column chromatography (ISCO, silica, 12 g, methanol in
dichloromethane) and result mixture of products was stirred in
acetonitrile (1 mL) with drops of 2M HCl (2 drops), diluted with 2M
sodium carbonate and extracted with dichloromethane (3.times.5 mL)
to provide compound 33 (9.1 mg, 19.94 .mu.mol, 64% yield).
[0378] Compound 34 and 35 were prepared according to General Method
K.
[0379] General Method O.
Preparation of
(3aR,13R,21aS)-7-fluoro-13-methyl-2,3,3a,11,12,13,14,21a-octahydro-1H,5H,-
15H-18,20-(metheno)cyclopenta[5,6][1,4]oxazino[4,3-e]pyrazolo[3,4-h]pyrido-
[2,3-b][1,5,7,11]oxatriazacyclotetradecin-15-one (36) and
(3aS,11S,20aR)-2-acetyl-7-fluoro-11-methyl-2,3,3a,12,13,20a-hexahydro-1H,-
5H-17,19-(metheno)pyrazolo[4,3-f]pyrido[3,2-l]pyrrolo[3',4':5,6][1,4]oxazi-
no[3,4-i][1,4,8,10]oxatriazacyclotridecin-14(11H)-one (37)
##STR00115##
[0381] Step 1. To a solution of A-6 (255.4 mg, 748.15 umol, racemic
mix) dissolved in anhydrous isopropanol (3.74 mL) at room
temperature. DIEA (290.08 mg, 2.24 mmol, 390.94 uL) was added
followed by C-1-5 (200.49 mg, 822.96 umol). The mixture stirred at
80.degree. C. for 18 hr and then concentrated under reduced
pressure. The crude was purified by flash column chromatography
(ISCO, silica, 12 g, ethyl acetate in hexanes) to afford 36-1
(142.1 mg, 259.05 umol, 34.63% yield).
[0382] Step 2. To a solution of 36-1 (142.1 mg, 259.05 umol) in
DMSO (1.30 mL) at room temperature, Cs.sub.2CO.sub.3 (168.81 mg,
518.10 umol) was added and the mixture was stirred at room
temperature for 72 hr. Diluted with water (15 mL) and extracted
with DCM (5 mL.times.5). The organic layer was back washed with
water (10 mL) and brine (10 mL), then dried over sodium sulfate.
The mixture was filtered and the filtrate was concentrated under
reduced pressure. The crude was purified by flash column
chromatography (ISCO, silica, 12 g, ethyl acetate in hexanes) to
afford 36-2 (78.1 mg, 147.77 umol, 57.04% yield).
[0383] To a solution of 36-2 (20.5 mg, 38.79 umol) in anhydrous DCM
(2 mL) was added HCl in dioxane (4 M, 1 mL). The mixture was
stirred at ambient temperature for 1 hr, concentrated under reduced
pressure, and dried under high vacuum to afford 36-3. Used directly
in subsequent step without further purification.
[0384] To crude 36-3 (14.5 mg, 33.85 umol) in DCM (338.46 uL) was
added acetic acid (3.05 mg, 50.77 umol, 2.90 uL) and Hunig's base
(21.87 mg, 169.23 umol, 29.48 uL) followed by FDPP (16.91 mg, 44.00
umol) in one portion. Let stir for 72 hr then quenched with 2 M
Na.sub.2CO3 solution (5 mL). Mixture was stirred for 5 min then
extracted with DCM (3.times.10 mL). Combined organic extracts were
dried with Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Flash chromatography (ISCO system, silica 12 g, methanol
in dichloromethane) provide 36-4 (9.9 mg, 21.04 umol, 62.18%
yield)
[0385] To a solution of 36-4 (9.9 mg, 21.04 umol) dissolved in
anhydrous ethanol (1 mL) was added HCl in dioxane (4 M, 1 mL). The
mixture was stirred at 70.degree. C. for 2 hr, then concentrated
under reduced pressure and dried under high vacuum to afford 36-5.
Used directly in subsequent step without further purification.
[0386] 36-5 was converted to compounds 36 and 37 as a racemic
mixture (cis) following the procedure used in General Method E. The
mixture was separated by flash column chromatography (ISCO, silica,
12 g, methanol in DCM) to provide 36 (1.23 mg, 2.63 umol, 26.89%
yield) and 37 (1.38 mg, 2.95 umol, 30.17% yield).
[0387] Compound 38, 39, 40, and 41 were prepared according to
General Method K.
[0388] Compound 42 was prepared according to General Method K using
rac trans-tert-butyl-3-hydroxycyclopentyl)carbamate and separating
from 41 after final step by flash column chromatography (ISCO,
silica, 12 g, ethyl acetate in hexanes)
[0389] Compound 43 was prepared according to General Method M.
Final product was purified by flash column chromatography (ISCO,
silica, 12 g, ethyl acetate in hexanes)
[0390] General Method P.
Preparation of ethyl
(5aS,8aR)-5,5a,6,7,8,8a-hexahydrocyclopenta[b]pyrazolo[1',5':1,2]pyrimido-
[4,5-e][1,4]oxazine-3-carboxylate (C-5)
##STR00116##
[0392] Step 1: (1R, 2S)-2-aminocyclopentanol, HCl (3.6 g, 26.16
mmol) was dissolved in anhydrous MeOH (96.89 mL) and treated with
strongly basic ion exchange resin (Amberlite IRN-78).
4-methoxybenzaldehyde (3.56 g, 26.16 mmol) was added and the
solution was stirred and heated to 65.degree. C. for 3 hr. The
mixture was cooled to room temperature and NaBH.sub.4 (989.68 mg,
26.16 mmol) was added. The reaction was stirred for 30 minutes,
then quenched with water (50 mL) and stirred for another 30
minutes. MeOH was removed under reduced pressure and the aqueous
phase was extracted with DCM (3.times.50 mL). The organic phase was
combined and dried over Na.sub.2SO.sub.4. The crude was purified by
flash chromatography (ISCO system, 80 g, 0-10% MeOH/DCM) to give
C-5-1 (4.92 g, 22.23 mmol, 84.98% yield)
[0393] Step 2: C-5-1 (2.6 g, 11.75 mmol), C-1-5 (2.5 g, 10.26 mmol)
and DIEA (4.56 g, 35.25 mmol, 6.14 mL) were dissolved in i-PA
(58.75 mL). The mixture was stirred at 80.degree. C. for 16 hr
after which volatiles were removed under reduced pressure. The
resulting crude was purified by flash column chromatography (ISCO,
silica, 80 g, 0-60% EtOAc in hexanes) to afford C-5-2 (2.1 g, 4.90
mmol, 41.72% yield).
[0394] Step 3: C-5-2 (2.1 g, 4.90 mmol) and Cs.sub.2CO.sub.3 (6.39
g, 19.61 mmol) were dissolved in DMSO (49.01 mL) and stirred at
room temperature for 3 hr. Diluted with water (500 mL) and
extracted with EtOAc (3.times.100 mL). The combined organic layer
was washed with 20% brine solution (3.times.100 mL) and dried over
Na.sub.2SO.sub.4. The crude was purified by flash chromatography
(ISCO, 80, 0-60% EtOAc in hexanes) to afford C-5-3 (1.69 g, 4.14
mmol, 84.42% yield).
[0395] C-5-3 (1.69 g, 4.14 mmol) was dissolved in TFA (41.38 mL)
and stirred at 75.degree. C. for 16 hr, the reaction was cooled to
room temperature and TFA was removed under reduced pressure. The
residue was treated with Sat. NaHCO.sub.3 and EtOAc (100 mL each)
and separated. The aqueous layer was extracted again with EtOAc
(2.times.50 mL) and the combined organic layer was dried over
Na.sub.2SO.sub.4. The crude was purified by flash column
chromatography (ISCO, silica, 80 g, 0-80% EtOAc in Hexanes) to
afford C-5 (1.12 g, 3.87 mmol, 93.47% yield)
[0396] Compounds C-6 and C-7 were prepared according to General
Method P using (1R, 2R)-2-aminocyclopentanol, HCl and (1S,
2S)-2-aminocyclopentanol, HCl respectively in step 1, and in high
dilution (30 mM in DMSO) in step 3.
TABLE-US-00006 MS [M + H] Compd# Structure m/z C-5 ##STR00117##
289.1 C-6 ##STR00118## 289.1 C-7 ##STR00119## 289.1
[0397] Compound 44 was prepared according to General Method I using
starting materials C-5 and D-2.
[0398] Compounds 45, 46, 47, and 48 was prepared according to
General Method K.
[0399] General Method Q
Preparation of
(3aR,11S,20aS)-7-fluoro-11-(hydroxymethyl)-2,3,3a,12,13,20a-hexahydro-1H,-
5H-17,19-(metheno)cyclopenta[5,6][1,4]oxazino[3,4-i]pyrazolo[4,3-f]pyrido[-
3,2-l][1,4,8,10]oxatriazacyclotridecin-14(11H)-one (49)
##STR00120##
[0401] Step 1. 49-1 (1.00 g, 13.50 mmol) was dissolved in THF (2.70
mL), water (2.70 mL) and methanol (21.60 mL). Ammonium chloride
(1.66 g, 31.05 mmol) was added followed by sodium azide (4.39 g,
67.50 mmol). The mixture was stirred at 75.degree. C. for 3 hr and
then cooled to ambient temperature. Volume was carefully reduced
under reduced pressure to a third and then diluted with DCM (50 mL)
and water (50 mL). The layers were partitioned and the aqueous
layer was extracted 2.times. with DCM (2.times.20 mL). The combined
organic layer was washed with brine and dried over sodium sulfate.
Flash column chromatography (ISCO, 24 g, silica, ethyl acetate in
hexanes) gave 49-2 (450.00 mg, 3.84 mmol, 28.46% yield)
[0402] Step 2. 49-2 (450.00 mg, 3.84 mmol) was dissolved in THF
(19.20 mL) and PPh.sub.3 (2.32 g, 8.83 mmol) was added. Stirred for
4 hr and water (1.59 g, 88.32 mmol, 1.59 mL) was added and
continued to stir for 16 hr when boc anhydride (1.09 g, 4.99 mmol)
was added followed by sodium bicarbonate (32.26 mg, 384.00 umol).
The mixture was stirred at RT for 4 hr and ethyl acetate and water
were added (30 mL each). The layers were partitioned and the
aqueous layer was extracted 2.times. with ethyl acetate (2.times.20
mL). The combined organic layer was washed with brine and then
dried over sodium sulfate. Purified by flash column chromatography
(ISCO, 24 g, silica, EtOAc in Hexanes) to provide 49-3 (525.30 mg,
2.75 mmol, 71.54% yield).
[0403] Step 3. 49-3 (525.86 mg, 2.75 mmol) was dissolved in DCM
(4.58 mL) and MOM-Cl (332.10 mg, 4.13 mmol, 313.30 uL) was added
followed by DIEA (710.82 mg, 5.50 mmol, 960.57 uL) at 0.degree. C.
Stirred for 18 hr slowly warming to RT. Water (5 mL) was added and
the layers were partitioned. The aqueous layer was extracted
2.times. with DCM (5 mL). The combined organic layer was washed
with brine and dried over sodium sulfate. Salts were filtered and
volatiles were carefully removed via rotary evaporation at
temperatures <30.degree. C. to afford 49-4 (132.2 mg, 0.561
mmol, 20% yield). Used directly without further purification.
[0404] Compound 49 was prepared according to General Method K using
49-4 and 5-3.
TABLE-US-00007 MS [M + H] Cpd Structure m/z .sup.1H NMR
(DMSO-d.sub.6) .delta. ppm 1 ##STR00121## 424.2 (500 MHz) 9.46 (dd,
J = 5.73, 4.01 Hz, 1 H) 8.55 (s, 1 H) 7.98 (s, 1 H) 7.36 (dd, J =
9.45, 3.15 Hz, 1 H) 7.07 - 7.13 (m, 1 H) 6.96 - 7.07 (m, 1 H) 5.30
- 5.40 (m, 1 H) 4.63 - 4.74 (m, 1 H) 4.58 (ddd, J = 10.45, 7.30,
2.86 Hz, 1 H) 4.53 (t, J = 4.01 Hz, 1 H) 4.21 (d, J = 14.89 Hz, 1
H) 3.82 (ddd, J = 13.46, 6.01, 4.58 Hz, 1 H) 3.18 - 3.24 (m, 1 H)
2.32 - 2.39 (m, 1 H) 2.10 - 2.20 (m, 1 H) 1.89 - 1.97 (m, 2 H) 1.69
- 1.79 (m, 1 H) 1.50 - 1.60 (m, 1 H) 1.44 (d. J = 6.30 Hz, 3 H) 2
##STR00122## 424.3 (300 MHz) 9.52 (br d, J = 5.78 Hz, 1 H) 8.63 (s,
1 H) 8.02 (s, 1 H) 7.21 (dd, J = 8.99 ,2.29 Hz, 1 H) 6.97 - 7.13
(m, 2 H) 5.46 (d, J = 15.04 Hz, 1 H) 4.45 - 4.59 (m, 1 H) 4.07 -
4.27 (m, 3 H) 3.86 - 3.99 (m, 1 H) 3.06 - 3.19 (m, 1 H) 1.63 - 2.22
(m, 5 H) 1.44 (d, J = 6.05 Hz, 3 H) 3 ##STR00123## 442.2 (500 MHz)
9.43 (t, J = 5.2 Hz, 1H), 8.58 (s, 1H), 7.99 (s, 1H), 7.25 - 7.11
(m, 2H), 5.30 (d, J = 14.8 Hz, 1H), 5.04 - 5.00 (m, 1H), 4.64 (t, J
= 3.8 Hz, 1H), 4.48 (ddd, J = 2.9, 7.3, 10.6 Hz, 1H), 4.26 (d, J =
15.1 Hz, 1H), 3.53 - 3.47 (m, 2H), 2.34 - 2.29 (m, 1H), 2.18 - 2.10
(m, 1H), 1.98 - 1.91 (m, 2H), 1.73 (brdd, J = 8.8, 17.8 Hz, 1H),
1.60 - 1.54 (m, 1H), 1.46 (d, J = 6.0 Hz, 3H) 4 ##STR00124## 426.2
(500 MHz) 9.40 (br t, J = 4.58 Hz, 1 H) 8.66 (s, 1 H) 8.02 (s, 1 H)
7.43 (dd, J = 9.45, 2.58 Hz, 1 H) 7.06 - 7.15 (m, 1 H) 6.98 - 7.06
(m, 1 H) 5.36 (d, J = 14.89 Hz, 1H) 4.96 - 5.07 (m, 1 H) 4.85 (br
s, 1H) 4.62 - 4.75 (m, 1 H) 4.33 (t, J = 7.45 Hz, 1 H) 4.16 - 4.29
(m, 2 H) 4.03 (d, J = 10.88 Hz, 1 H) 3.77 - 3.86 (m, 1 H) 3.57 (t,
J = 8.88 Hz, 1 H) 3.19 - 3.24 (m, 1 H) 1.44 (d, J = 5.73 Hz, 3H) 5
##STR00125## 425.3 (300 MHz) 9.36 - 9.45 (m, 1 H) 8.55 (s, 1 H)
8.07 (d, J = 2.93 Hz, 1 H) 7.93 - 8.02 (m, 2 H) 5.10 - 5.27 (m, 2
H) 4.60 (ddd, J = 10.45, 7.34, 3.30 Hz, 1 H) 4.48 - 4.54 (m, 1 H)
4.33 (d, J = 14.95 Hz, 1 H) 3.93 (ddd, J = 12.95, 8.05, 4.49 Hz, 1
H) 3.09 - 3.21 (m, 1 H) 2.29- 2.40 (m, 1 H) 2.06 - 2.17 (m, 1H)
1.86-2.00 (m, 2 H) 1.66 - 1.80 (m, 1 H) 1.49 -1.63 (m, 1 H) 1.45
(d, J = 6.14 Hz, 3 H) 6 ##STR00126## 425.1 (500 MHz) 9.53 (d, J =
8.02 Hz, 1 H) 8.55 (s, 1 H) 8.09 (d, J = 2.86 Hz, 1 H) 8.03 (dd, J
= 8.59, 2.86 Hz, 1 H) 7.99 (s, 1 H) 5.32 (d, J = 14.89 Hz, 1 H)
4.70 (dd, J = 10.88, 4.01 Hz, 1 H) 4.61 (ddd, J = 10.45, 7.30, 3.44
Hz, 1 H) 4.48 (t, J = 4.01 Hz, 1 H) 4.35 (d, J = 14.89 Hz, 1H) 4.26
(br dd, J = 11.17, 6.59 Hz, 1 H) 4.14 (dd, J = 10.60, 1.43 Hz, 1 H)
2.33 - 2.43 (m, 1 H) 2.07 - 2.19 (m, 1 H) 1.88 - 1.98 (m, 2 H) 1.69
- 1.82 (m, 1 H) 1.50 - 1.62 (m, 1 H) 1.36 (d, J = 6.87 Hz, 3 H) 7
##STR00127## 442.1 (500 MHz) 9.89 (br d, J = 8.59 Hz, 1 H) 8.58 (s,
1 H) 8.01 (s, 1 H) 7.19 - 7.30 (m, 2 H) 5.46 (br d, J = 14.89 Hz, 1
H) 4.74 (br dd, J = 9.45, 6.01 Hz, 1 H) 4.53 - 4.64 (m, 2 H) 4.25
(br d, J = 15.47 Hz, 1 H) 4.20 (br t, J = 7.16 Hz, 1 H) 3.93 - 4.05
(m, 1 H) 2.31 - 2.40 (m, 1 H) 2.09 - 2.20 (m, 1 H) 1.87 - 1.97 (m,
2 H) 1.68 - 1.79 (m, 1 H) 1.48 - 1.59 (m, 1 H) 1.33 (d, J = 6.87
Hz, 3 H) 8 ##STR00128## 411.1 9.37 (br d, J = 6.30 Hz, 1 H) 8.62
(s, 1 H) 8.06 (d, J = 2.86 Hz, 1 H) 8.01 (s, 1 H) 7.90 (dd, J =
8.88, 2.58 Hz, 1H) 5.26 (d, J = 15.47 Hz, 1 H) 5.11 - 5.20 (m, 1 H)
5.05 (q, J = 6.87 Hz, 1 H) 4.91 (br d, J = 2.86 Hz, 1 H) 4.14 (d, J
= 14.89 Hz, 1 H) 3.93 - 4.02 (m, 1 H) 3.07 - 3.19 (m, 1 H) 2.28 -
2.35 (m, 1 H) 2.11 - 2.22 (m, 1 H) 2.02 - 2.09 (m, 1 H) 1.94 - 2.02
(m, 1 H) 1.46 (d, J = 6.30 Hz, 3 H) 9 ##STR00129## 411.0 9.38 (br
d, J = 5.73 Hz, 1 H) 8.68 (s, 1 H) 8.08 (d, J = 2.86 Hz, 1 H) 8.03
(s, 1 H) 7.42 (dd, J = 8.59, 2.86 Hz, 1H) 5.34 (br d, J = 14.89 Hz,
1 H) 5.10 - 5.21 (m, 1 H) 4.74 (br d, J = 2.29 Hz, 1 H) 4.37 - 4.48
(m, 1 H) 4.24 (d, J = 14.89 Hz, 1 H) 3.96 (ddd, J = 13.03, 8.16,
4.58 Hz, 1 H) 3.11 - 3.20 (m, 1 H) 2.60 - 2.72 (m, 1 H) 2.41 - 2.48
(m, 1 H) 2.19 - 2.31 (m, 1 H) 2.00 - 2.08 (m, 1 H) 1.46 (d, J =
6.30 Hz, 3 H) 10 ##STR00130## 411.0 (500 MHz) 9.43 (d, J = 8.02 Hz,
1 H) 8.62 (s, 1 H) 8.07 (d, J = 2.86 Hz, 1 H) 8.01 (s, 1 H) 7.93
(dd, J = 8.59, 2.86 Hz, 1 H) 5.34 (dd, J = 14.89, 1.15 Hz, 1 H)
5.03 (q, J = 6.68 Hz, 1 H) 4.90 (dt, J = 5.73, 2.86 Hz, 1 H) 4.75
(dd, J = 10.60, 4.30 Hz, 1 H) 4.25 - 4.34 (m, 1 H) 4.16 (d, J =
10.88 Hz, 1 H) 4.13 (dd, J = 9.17, 1.72 Hz, 1 H) 2.27 - 2.35 (m, 1
H) 2.13 - 2.22 (m, 1 H) 2.05 - 2.13 (m, 1 H) 1.98 - 2.05 (m, 1 H)
1.38 (d. J = 6.87 Hz, 3 H) 11 ##STR00131## 411.0 (500 MHz) 9.47 (d,
J = 8.02 Hz, 1 H) 8.68 (s, 1 H) 8.10 (d, J = 3.44 Hz, 1 H) 8.03 (s,
1 H) 7.49 (dd, J = 8.59, 2.86 Hz, 1 H) 5.45 (d, J = 16.04 Hz, 1 H)
4.73 (br d, J = 4.01 Hz, 1 H) 4.70 (dd, J = 10.88, 4.01 Hz, 1 H)
4.42 - 4.48 (m, 1 H) 4.24 - 4.31 (m, 2 H) 4.15 (dd, J = 10.60, 2.00
Hz, 1 H) 2.65 - 2.73 (m, 1 H) 2.42 (dt, J = 18.62, 9.59 Hz, 1 H)
2.19 - 2.28 (m, 1 H) 1.98 - 2.04 (m, 1 H) 1.37 (d, J = 6.30 Hz, 3
H) 12 ##STR00132## 439.1 (500 MHz) 9.41 (br d, J = 7.45 Hz, 1 H)
8.55 (s, 1 H) 8.06 (br s, 1 H) 7.97 (d, J = 1.72 Hz, 1 H) 7.95 (br
d, J = 9.17 Hz, 1 H) 5.07 - 5.20 (m, 2 H) 4.50 (br s, 1 H) 4.33 (br
d, J = 14.89 Hz, 1 H) 4.26 (br s, 1 H) 3.87 - 3.99 (m, 1 H) 3.09 -
3.19 (m, 1 H) 2.06 - 2.17 (m, 2 H) 1.87 (br t, J = 12.32 Hz, 1 H)
1.78 (br d, J = 1.15 Hz, 1 H) 1.47 - 1.60 (m, 2H) 1.45 (br d, J =
5.73 Hz, 3 H) 1.41 (br d, J = 8.59 Hz, 2H) 13 ##STR00133## 439.1
(500 MHz) 9.51 (d, J = 8.59 Hz, 1 H) 8.54 (s, 1 H) 8.08 (d, J =
3.44 Hz, 1 H) 8.00 (dd, J = 9.16, 2.86 Hz, 1 H) 7.97 (s, 1 H) 5.21
(dd, J = 14.89,1.15 Hz, 1 H) 4.70 (dd, J = 10.60, 4.30 Hz, 1 H)
4.47 (br s, 1 H) 4.35 (d, J = 14.89 Hz, 1 H) 4.21 - 4.31 (m, 2 H)
4.14 (dd, J = 10.31, 1.72 Hz, 1 H) 2.07 - 2.19 (m, 2H) 1.83 -1.92
(m, 1 H) 1.78 (br s, 1 H) 1.38 - 1.59 (m, 4 H) 1.36 (d, J = 6.30
Hz, 3 H) 14 ##STR00134## 451.1 (500 MHz) 9.73 (d, J = 9.16 Hz, 1 H)
8.55 (s, 1 H) 8.10 (d, J = 2.86 Hz, 1 H) 8.05 (dd, J = 8.59, 2.86
Hz, 1 H) 7.99 (s, 1 H) 5.30 - 5.38 (m, 1 H) 4.64 - 4.69 (m, 1 H)
4.58 - 4.64 (m, 1 H) 4.47 (t, J = 3.72 Hz. 1 H) 4.37 (d, J = 8.02
Hz, 1 H) 4.34 (d, J = 4.01 Hz, 1 H) 3.75 (td, J = 8.59, 4.01 Hz, 1
H) 2.33 - 2.44 (m, 1 H) 2.07 - 2.19 (m, 1 H) 1.86 - 1.99 (m, 2 H)
1.67 - 1.81 (m, 1 H) 1.51 - 1.63 (m, 1 H) 1.20 - 1.33 (m, 1 H) 0.42
- 0.55 (m, 3 H) 0.27 - 0.37 (m, 1 H) 15 ##STR00135## 439.1 (500
MHz) 8.52 (s, 1 H) 8.11 (t, J = 4.30 Hz, 1 H) 8.04 (d, J = 2.86 Hz,
1 H) 7.99 (s, 1 H) 7.86 (dd, J = 8.59, 2.86 Hz, 1 H) 5.55 (br t, J
= 6.59 Hz, 1 H) 5.28 (dd, J = 14.89, 1.15 Hz, 1 H) 4.54 - 4.58 (m,
1 H) 4.50 - 4.54 (m, 1 H) 4.29 (d, J = 14.89 Hz, 1 H) 3.61 - 3.68
(m, 1 H) 3.34 - 3.37 (m, 1 H) 2.32 - 2.38 (m, 1 H) 2.09 - 2.16 (m,
2 H) 1.88 - 1.97 (m, 3 H) 1.69 - 1.76 (m, 1 H) 1.51 - 1.59 (m, 1 H)
1.30 (d, J = 6.30 Hz, 3 H) 16 ##STR00136## 439.1 (500 MHz) 8.55 (s,
1 H) 8.48 (s, 1 H) 8.14 (d, J = 6.87 Hz, 1 H) 8.05 - 8.09 (m, 2 H)
7.92 (dd, J = 8.59, 2.86 Hz, 1 H) 7.44 (dd, J = 8.59, 2.86 Hz, 1 H)
5.54 (t, J = 12.03 Hz, 1 H) 5.30 - 5.42 (m, 2 H) 4.76 - 4.83 (m, 1
H) 4.47 - 4.56 (m, 2 H) 4.17 - 4.38 (m, 5 H) 4.05 (ddd, J = 10.60,
6.87, 3.72 Hz, 1 H) 3.91 - 3.97 (m, 1 H) 2.50 - 2.56 (m, 1 H) 2.06
- 2.38 (m, 5 H) 1.82 - 2.00 (m, 6 H) 1.62 - 1.75 (m, 2 H) 1.18 (d,
J = 6.30 Hz, 3 H) 17 ##STR00137## 439.1 (500 MHz) 8.60 (s, 1 H)
8.53 (s, 1 H) 8.17 - 8.22 (m, 1 H) 8.06 (d, J = 2.86 Hz, 1 H) 8.02
(s, 1 H) 7.99 (s, 1 H) 7.87 (dd, J = 8.88, 2.58 Hz, 1 H) 7.56 (dd,
J = 8.59, 3.44 Hz, 1 H) 5.27 (dd, J = 14.89, 1.15 Hz, 1 H) 4.92 -
4.96 (m, 1 H) 4.51 - 4.57 (m, 2 H) 4.31 (d, J = 15.47 Hz, 1 H) 3.95
(dd, J = 11.17, 8.88 Hz, 1 H) 3.88 (br dd, J = 13.17, 8.02 Hz, 1 H)
3.06 (ddd, J = 13.75, 8.59, 2.86 Hz, 1 H) 2.30 - 2.38 (m, 2 H) 2.09
- 2.16 (m, 1 H) 1.90 - 1.98 (m, 2 H) 1.69 - 1.77 (m, 1 H) 1.52 -
1.60 (m. 1 H) 1.03 (d, J = 6.87 Hz, 3 H) 18 ##STR00138## 437.1 (500
MHz) 9.02 - 9.15 (m, 1 H) 8.47 - 8.63 (m, 1 H) 8.07 (d, J = 2.86
Hz, 1 H) 8.02 (dd, J = 8.88, 2.58 Hz, 1 H) 7.90 - 7.96 (m, 1 H)
5.34 - 5.56 (m, 1 H) 4.79 - 4.91 (m, 1 H) 4.60 (ddd, J = 10.74,
7.30, 3.15 Hz, 1 H) 4.46 (t, J = 3.72 Hz, 1 H) 4.26 - 4.36 (m, 1 H)
3.71 - 3.85 (m, 1 H) 2.32 - 2.41 (m, 1 H) 2.06 - 2.20 (m, 1 H) 1.87
- 2.03 (m, 3 H) 1.67 - 1.82 (m, 1 H) 1.51 - 1.63 (m, 1 H) 0.99 -
1.11 (m, 1 H) 0.90 - 0.98 (m, 1 H) 0.73 - 0.87 (m, 1 H) 19
##STR00139## 425.1 (500 MHz) 8.60 (s, 1 H) 8.53 (s, 1 H) 8.09 -
8.14 (m, 1 H) 8.06 (d, J = 2.86 Hz, 1 H) 8.00 (s, 1 H) 7.89 (dd, J
= 9.17, 2.86 Hz, 1 H) 7.50 (dd, J = 8.59, 2.29 Hz, 1 H) 5.32 (dd, J
= 14.89, 1.15 Hz, 1 H) 4.95 - 5.05 (m, 1 H) 4.51 - 4.59 (m, 2 H)
4.27 - 4.33 (m, 1 H) 4.17 - 4.24 (m, 1 H) 3.67 - 3.74 (m, 1 H) 3.35
- 3.41 (m, 1 H) 2.30 - 2.40 (m, 1 H) 2.10 - 2.18 (m, 2 H) 1.86 -
2.04 (m, 5 H) 1.65 - 1.79 (m, 1 H) 1.48-1.61 (m, 1 H) 20
##STR00140## 451.1 (500 MHz) 8.87 (t, J = 5.16 Hz, 1 H) 8.63 (s, 1
H) 8.05 (d, J = 2.86 Hz, 1 H) 8.01 (s, 1 H) 7.61 (dd, J = 8.88,
2.58 Hz, 1 H) 5.30 - 5.38 (m, 1 H) 4.93 (dd, J = 15.18, 1.43 Hz, 1
H) 4.53 (d, J = 15.47 Hz, 1 H) 4.20 - 4.33 (m, 2 H) 3.81 (dt, J =
13.17, 4.87 Hz, 1 H) 3.22 - 3.31 (m, 1 H) 1.61 (s, 3 H) 1.45 (d, J
= 6.30 Hz, 3 H) 1.36 (s, 3 H) 21 ##STR00141## 439.1 (500 MHz) 9.09
(s, 1 H) 8.51 - 8.63 (m, 1 H) 8.06 - 8.14 (m, 2 H) 7.94 - 7.99 (m,
1 H) 5.31 - 5.59 (m, 1 H) 4.56 - 4.71 (m, 2 H) 4.47 (t, J = 3.81
Hz, 1 H) 4.32 (br d, J = 14.67 Hz, 1 H) 3.90 - 3.98 (m, 1 H) 2.36 -
2.44 (m, 1 H) 2.08 - 2.18 (m, 1 H) 1.89 - 1.98 (m, 2 H) 1.70 - 1.82
(m, 1 H) 1.62 (s, 3 H) 1.53 - 1.59 (m, 1 H) 1.49 (s, 3 H) 22
##STR00142## 451.2 (500 MHz) 8.94 - 9.12 (m, 1 H) 8.49 - 8.65 (m, 1
H) 8.11 (d, J = 2.86 Hz, 1 H) 8.06 (dd, J = 8.59, 2.29 Hz, 1 H)
7.94 - 8.02 (m, 1 H) 5.21 - 5.48 (m, 1 H) 4.74 - 4.95 (m, 1 H) 4.54
- 4.64 (m, 1 H) 4.46 (t, J = 3.44 Hz, 1 H) 4.32 - 4.40 (m, 1 H)
4.23 - 4.32 (m, 1 H) 3.38 - 3.60 (m, 1 H) 2.65 - 2.84 (m, 1 H) 2.34
- 2.44 (m, 1 H) 2.16 - 2.26 (m, 1 H) 2.02 - 2.16 (m, 2 H) 1.77 -
1.99 (m, 4 H) 1.66 - 1.77 (m, 1 H) 1.48 - 1.62(m, 1 H) 23
##STR00143## 465.2 (500 MHz) 8.47 - 8.64 (m, 1 H) 8.04 - 8.13 (m, 2
H) 7.99 - 8.04 (m, 1 H) 7.51 - 7.97 (m, 1 H) 5.26 - 5.46 (m, 1 H)
5.06 - 5.25 (m, 1 H) 4.53 - 4.60 (m, 1 H) 4.51 (t, J = 3.72 Hz, 1
H) 4.23 - 4.34 (m, 1 H) 4.04 - 4.14 (m, 1 H) 3.68 - 3.79 (m, 1 H)
2.31 - 2.41 (m, 1 H) 2.10 - 2.22 (m, 2 H) 1.87 - 2.04 (m, 7 H) 1.77
- 1.85 (m, 1 H) 1.66 - 1.75 (m, 1H) 1.49-1.61 (m, 1 H) 24
##STR00144## 451.2 (500 MHz) 9.31 (d, J = 6.87 Hz, 1 H) 8.54 (s, 1
H) 8.04 (d, J = 2.86 Hz, 1 H) 7.97 (s, 1 H) 7.95 (dd, J = 8.88,
2.58 Hz, 1 H) 5.73 (td, J = 6.30, 3.44 Hz, 1 H) 5.22 (d, J = 14.89
Hz, 1 H) 4.57 (ddd, J = 10.45, 7.30, 3.44 Hz, 1 H) 4.51 (t, J =
4.01 Hz, 1 H) 4.34 (d, J = 14.89 Hz, 1 H) 4.25 (quin, J = 7.02 Hz,
1 H) 2.31 - 2.40 (m, 1 H) 2.03 - 2.21 (m, 3 H) 1.89 - 1.98 (m, 2 H)
1.78 - 1.89 (m, 2 H) 1.67 - 1.78 (m, 2 H) 1.51 - 1.65 (m, 2H) 25
##STR00145## 487.1 (500 MHz) 8.94 - 9.15 (m, 1 H) 8.52 - 8.67 (m, 1
H) 8.12 (d, J = 2.29 Hz, 1 H) 8.02 - 8.09 (m, 1 H) 7.93 - 8.02 (m,
1 H) 5.20 - 5.43 (m, 1 H) 4.99 - 5.12 (m, 1 H) 4.59 (ddd, J =
10.45, 7.59, 3.15 Hz, 1 H) 4.47 (t, J = 3.72 Hz, 1 H) 4.25 - 4.36
(m, 2 H) 3.89 - 4.19 (m, 1 H) 3.57 - 3.85 (m, 1 H) 2.99 - 3.21 (m,
1 H) 2.74 - 2.87 (m, 1 H) 2.34 - 2.44 (m, 1 H) 2.06 - 2.21 (m, 1 H)
1.88 - 1.99 (m, 2 H) 1.69 - 1.82 (m, 1 H) 1.48-1.61 (m, 1H) 26
##STR00146## 465.2 (500 MHz) 9.19 (s, 1 H) 8.47 - 8.64 (m, 1 H)
8.04 - 8.18 (m, 2 H) 7.92 - 8.01 (m, 1 H) 5.26 - 5.59 (m, 1 H) 4.52
- 4.71 (m, 2 H) 4.46 (t, J = 4.01 Hz, 1 H) 4.23 - 4.36 (m, 1 H)
3.95 - 4.07 (m, 1 H) 2.87 (ddd, J = 13.32, 9.02, 4.01 Hz, 1 H) 2.31
- 2.45 (m, 1 H) 2.06 - 2.17 (m, 1 H) 1.85 - 2.06 (m, 5 H) 1.63 -
1.85 (m, 3 H) 1.50 - 1.63 (m, 2 H) 1.39- 1.50 (m, 1 H) 27
##STR00147## 419.2 (500 MHz) 8.49 - 8.62 (m, 1 H) 8.12 - 8.26 (m, 1
H) 7.92 - 8.09 (m, 3 H) 5.31 - 5.51 (m, 1 H) 5.00 - 5.18 (m, 1 H)
4.57 (ddd, J = 10.60, 7.45, 3.15 Hz, 1 H) 4.50 - 4.53 (m, 1 H) 4.29
- 4.34 (m, 1 H) 3.65 - 3.72 (m, 1 H) 3.42 - 3.49 (m, 1H) 3.13 (dd,
J = 13.75, 2.29 Hz, 1H) 2.32 - 2.40 (m, 1 H) 2.08 - 2.19 (m, 1 H)
1.88 - 1.99 (m, 2 H) 1.68 - 1.78 (m, 1 H) 1.51 -1.63 (m, 1 H) 1.21
(s, 3H) 1.02 (s, 3H) 28 ##STR00148## 439.1 (500 MHz) 8.49 - 8.61
(m, 1 H) 7.98 - 8.19 (m, 3 H) 7.45 - 7.97 (m, 1 H) 4.75 - 5.66 (m,
2 H) 4.49 - 4.61 (m, 1 H) 4.18 - 4.43 (m, 3 H) 3.92 - 4.14 (m, 1 H)
2.53 - 2.66 (m, 1 H) 2.09 - 2.40 (m, 2 H) 1.46 - 2.01 (m, 5 H) 1.23
(dd, J = 18.33, 6.87 Hz, 3 H) 29 ##STR00149## 414.3 (500 MHz) 8.50
- 8.64 (m, 1 H) 8.18 - 8.28 (m, 1 H) 7.99 - 8.09 (m, 2 H) 7.83 -
7.98 (m, 1 H) 5.23 - 5.42 (m, 1 H) 4.78 -4.99 (m, 1 H) 4.49 - 4.61
(m, 2 H) 4.26 - 4.34 (m, 1 H) 3.92 - 4.00 (m, 1 H) 3.57 - 3.91 (m,
1 H) 2.97 - 3.12 (m, 1 H) 2.29 - 2.39 (m, 2 H) 2.07-2.18 (m, 1 H)
1.87-2.00 (m, 2 H) 1.66 - 1.79 (m, 1 H) 1.49 - 1.61 (m, 1 H) 1.03
(dd, J = 6.87, 2.86 Hz, 3 H) 30 ##STR00150## 427.1 (500 MHz) 9.33 -
9.37 (m, 1 H) 8.67 (s, 1 H) 8.08 (d, J = 2.86 Hz, 1 H) 8.02 - 8.06
(m, 2 H) 5.23 (d, J = 15.47 Hz, 1 H) 5.14 - 5.20 (m, 1 H) 5.01 -
5.07 (m, 1 H) 4.82 (t, J = 3.44 Hz, 1 H) 4.30 - 4.40 (m, 2 H) 4.19
(dd, J = 10.31, 3.44 Hz, 1 H) 4.03 (d, J = 10.88 Hz, 1 H) 3.90 -
3.97 (m, 1 H) 3.53 - 3.59 (m, 1 H) 3.15 (ddd, J = 13.60, 8.74, 2.86
Hz, 1 H) 1.45 (d, J = 5.73 Hz, 3 H) 31 ##STR00151## 427.1 (500 MHz)
9.24 (dd, J = 6.59, 3.15 Hz, 1 H) 8.75 (s, 1 H) 8.04 - 8.09 (m, 2
H) 7.39 (dd, J = 8.59, 2.86 Hz, 1 H) 5.37 (d, J = 14.89 Hz, 1 H)
5.21 - 5.28 (m, 1 H) 4.65 (t, J = 3.72 Hz, 1 H) 4.61 (t, J = 7.16
Hz, 1 H) 4.46 - 4.51 (m, 1 H) 4.35 (d, J = 14.89 Hz, 1 H) 4.29 (dd,
J = 10.88, 4.58 Hz, 1 H) 4.03 (d, J = 10.31 Hz, 1 H) 3.88 - 3.95
(m, 1 H) 3.80 - 3.85 (m, 1 H) 3.17 - 3.24 (m, 1 H) 1.46 (d, J =
6.30 Hz, 3 H) 32 ##STR00152## 441.0 (500 MHz) 8.53 (s, 1 H) 8.13
(dd, J = 8.59, 1.72 Hz, 1 H) 8.05 (d, J = 2.86 Hz, 1 H) 7.99 (s, 1
H) 7.85 (dd, J = 8.59, 2.86 Hz, 1 H) 5.37 (d, J = 4.58 Hz, 1 H)
5.28 (dd, J = 15.18, 1.43 Hz, 1 H) 5.01 (br d, J = 9.74 Hz, 1 H)
4.49 - 4.58 (m, 2 H) 4.30 (d, J = 15.47 Hz, 1 H) 4.00 - 4.10 (m, 2
H) 3.91 - 3.98 (m, 1 H) 3.12 (ddd, J = 13.17, 8.59, 2.29 Hz, 1 H)
2.29 - 2.38 (m, 1 H) 2.07 - 2.19 (m, 1 H) 1.86- 1.98 (m, 2 H) 1.66
- 1.76 (m, 1H) 1.48 - 1.59 (m, 1 H) 33 ##STR00153## 457.0 34
##STR00154## 453.2 (500 MHz) 8.45 - 8.58 (m, 1 H) 8.08 (d, J = 2.86
Hz, 1 H) 7.96 - 8.02 (m, 2 H) 7.81 - 7.89 (m, 1 H) 5.39 - 5.57 (m,
1 H) 4.89 - 5.15 (m, 1 H) 4.54 - 4.60 (m, 1 H) 4.44 (t, J = 3.72
Hz, 1 H) 4.24
(d, J = 15.47 Hz, 1 H) 4.06 (br dd, J = 11.17, 5.44 Hz, 1 H) 1.66 -
2.44 (m, 8 H), 1.54 - 1.58 (m, 3 H) 1.50 - 1.53 (m, 3 H) 35
##STR00155## 439.2 (500 MHz) 8.59 (s, 1 H) 8.52 (s, 1 H) 8.09 (br
t, J = 4.58 Hz, 1 H) 8.03 (d, J = 2.86 Hz, 1 H) 8.00 (s, 1 H) 7.44
(dd, J = 8.59, 2.86 Hz, 1 H) 5.62 (br t, J = 6.30 Hz, 1 H) 5.40
(dd, J = 15.18, 1.43 Hz, 1 H) 4.23 - 4.31 (m, 2 H) 4.06 (ddd, J =
10.60, 6.87, 3.72 Hz, 1 H) 3.56 - 3.65 (m, 1 H) 2.52 - 2.57 (m, 1
H) 2.14 - 2.27 (m, 2 H) 1.86 - 2.01 (m, 5 H) 1.66 - 1.74 (m, 1 H)
1.29 - 1.33 (m, 4 H) 36 ##STR00156## 468.2 (500 MHz) 9.38 (br d, J
= 4.01 Hz, 1 H) 8.68 (d, J = 9.74 Hz, 1 H) 8.09 (t, J = 2.58 Hz, 1
H) 7.97 - 8.05 (m, 2 H) 4.98 - 5.27 (m, 3 H) 4.78 - 4.88 (m, 1 H)
4.22 - 4.44 (m, 2 H) 3.80 - 3.99 (m, 2 H) 3.67 - 3.69 (m, 1 H) 3.03
- 3.19 (m, 2 H) 2.00 (d, J = 7.45 Hz, 3 H) 1.46 (d, J = 6.30 Hz, 3
H) 37 ##STR00157## 468.2 (500 MHz) 9.17 - 9.24 (m, 1 H) 8.75 (d, J
= 13.75 Hz, 1 H) 8.10 (t, J = 3.15 Hz, 1 H) 8.05 - 8.08 (m, 1 H)
7.39 - 7.57 (m, 1H) 5.35 - 5.44 (m, 1 H) 5.21 - 5.30 (m, 1 H) 4.28
- 4.73 (m, 4 H) 3.62 - 4.02 (m, 4 H) 3.19 - 3.24 (m, 1 H) 2.01 -
2.10 (m, 3 H) 1.46 (d, J = 6.30 Hz, 3 H) 38 ##STR00158## 443.2 (500
MHz) 8.54 (s, 1 H) 8.19 (t, J = 4.87 Hz, 1 H) 8.09 (d, J = 2.86 Hz,
1 H) 8.01 (s, 1 H) 7.94 (dd, J = 8.88, 2.58 Hz, 1 H) 5.30 - 5.41
(m, 1 H) 5.27 (dd, J = 14.89, 1.15 Hz, 1 H) 5.07 - 5.21 (m, 1 H)
4.50 - 4.58 (m, 2 H) 4.30 - 4.39 (m, 2 H) 3.93 - 4.02 (m, 1 H) 3.56
- 3.69 (m, 1 H) 2.30 - 2.39 (m, 1 H) 2.09 - 2.18 (m, 1 H) 1.89 -
1.99 (m, 2 H) 1.65 - 1.79 (m, 1 H) 1.50 - 1.65 (m. 1 H) 39
##STR00159## 443.2 (500 MHz) 8.53 - 8.62 (m, 1 H) 8.10 - 8.27 (m, 1
H) 8.08 (t, J = 2.58 Hz, 1 H) 8.02 (d, J = 2.29 Hz, 1 H) 7.49 -
7.97 (m, 1H) 5.44 - 5.53 (m, 1 H) 5.33 - 5.43 (m, 1 H) 5.00 - 5.21
(m, 1 H) 4.52 - 4.60 (m, 1 H) 4.22 - 4.41 (m, 3 H) 3.95 - 4.14 (m,
1 H) 3.52 - 3.67 (m, 1 H) 2.32 - 2.40 (m, 1 H) 2.09 - 2.27 (m, 1 H)
1.87 - 2.00 (m, 2 H) 1.66 - 1.78 (m, 1 H) 1.46 - 1.58 (m, 1 H) 40
##STR00160## 461.1 (500 MHz) 8.53 - 8.62 (m, 1 H) 8.10 - 8.27 (m, 1
H) 8.08 (t, J = 2.58 Hz, 1 H) 8.02 (d, J = 2.29 Hz, 1 H) 7.49 -
7.97 (m, 1H) 5.44 - 5.53 (m, 1 H) 5.33 - 5.43 (m, 1 H) 5.00 - 5.21
(m, 1 H) 4.52 - 4.60 (m, 1 H) 4.22 - 4.41 (m, 3 H) 3.95 - 4.14 (m,
1 H) 3.52 - 3.67 (m, 1 H) 2.32 - 2.40 (m, 1 H) 2.09 - 2.27 (m, 1 H)
1.87 - 2.00 (m, 2 H) 1.66 - 1.78 (m, 1 H) 1.46 - 1.58 (m, 1 H) 41
##STR00161## 10-840 (300 MHz) 8.34 - 8.67 (m, 2 H) 7.94 - 8.19 (m,
2 H) 7.48 (dd, J = 8.67, 2.61 Hz, 1 H) 5.38 - 5.62 (m, 1 H) 5.18 -
5.38 (m, 1 H) 4.50 - 4.85 (m, 1 H) 4.17 - 4.49 (m, 2 H) 3.97 - 4.14
(m, 1 H) 1.60 - 2.43 (m, 12 H) 42 ##STR00162## 451.2 (300 MHz) 8.53
(s, 1 H) 8.41 (d, J = 10.55 Hz, 1 H) 8.07 (d, J = 2.93 Hz, 1 H)
7.98 (s, 1 H) 7.86 (dd, J = 8.89, 2.66 Hz, 1 H) 5.37 (br s, 1 H)
5.23 - 5.32 (m, 1 H) 4.69 - 4.84 (m, 1 H) 4.49 - 4.61 (m, 2 H) 4.31
(br d, J = 15.31 Hz, 1 H) 2.23 - 2.39 (m, 2 H) 2.01 - 2.19 (m, 4 H)
1.67 - 1.96 (m, 5 H) 1.50 - 1.64 (m, 1 H) 43 ##STR00163## 441.2
(300 MHz) 8.50 - 8.67 (m, 1 H) 7.36 - 8.20 (m, 4 H) 5.21 - 5.52 (m,
2 H) 4.85 - 5.11 (m, 1 H) 3.70 - 4.67 (m, 6 H) 2.97 - 3.19 (m, 1 H)
2.03 - 2.42 (m, 2 H) 1.87 - 2.02 (m, 2 H) 1.66 - 1.83 (m, 1 H) 1.56
(br d, J = 10.73 Hz, 1H) 44 ##STR00164## 425.1 (300 MHz) 9.40 (dd,
J = 7.61, 2.11 Hz, 1 H) 8.55 (s, 1 H) 8.07 (d, J = 2.93 Hz, 1 H)
7.94 - 8.02 (m, 2 H) 5.11 - 5.27 (m, 2 H) 4.60 (ddd, J = 10.41,
7.34, 3.16 Hz, 1 H) 4.51 (t, J = 3.76 Hz, 1 H) 4.33 (d, J = 14.95
Hz, 1 H) 3.86 - 4.01 (m, 1 H) 3.15 (ddd, J = 13.25, 8.76, 2.57 Hz,
1 H) 2.28 - 2.42 (m, 1 H) 2.03 - 2.22 (m, 1 H) 1.85 - 2.00 (m, 2 H)
1.66 - 1.82 (m, 1 H) 1.49 - 1.64 (m, 1 H) 1.45 (d, J = 6.24 Hz, 3
H) 45 ##STR00165## 465.2 (300 MHz) 8.43 - 8.62 (m, 1 H) 7.86 - 8.13
(m, 4 H) 5.35 - 5.56 (m, 1 H) 4.65 - 4.93 (m, 1 H) 4.49 - 4.62 (m,
1 H) 4.40 - 4.48 (m, 1 H) 4.25 (br d, J = 14.40 Hz, 1 H) 4.06 -
4.17 (m, 1 H) 3.15 - 3.27 (m, 2 H) 2.09 - 2.35 (m, 4 H) 1.84 - 2.00
(m, 4 H) 1.67 - 1.77 (m, 3 H) 1.46 - 1.58 (m, 1 H) 46 ##STR00166##
437.1 (300 MHz) 8.97 - 9.10 (m, 1 H) 8.53 - 8.68 (m, 1 H) 7.96 -
8.11 (m, 3 H) 5.44 - 5.59 (m, 1 H) 5.12 (q, J = 4.49 Hz, 1 H) 4.50
- 4.71 (m, 3 H) 4.24 - 4.42 (m, 1 H) 2.79 - 3.10 (m, 2 H) 2.30 -
2.42 (m, 1 H) 2.03 - 2.22 (m, 2 H) 1.87 - 2.01 (m, 2 H) 1.49 - 1.82
(m, 3 H) 47 ##STR00167## 461.1 (300 MHz) 9.83 (d, J = 9.08 Hz, 1 H)
8.59 (s, 1 H) 8.11 (d, J = 2.84 Hz, 1 H) 8.00 - 8.08 (m, 2 H) 6.10
- 6.56 (m, 1 H) 5.32 (dd, J = 14.76, 1.38 Hz, 1 H) 4.87 (br dd, J =
11.60, 4.81 Hz, 1 H) 4.52 - 4.67 (m, 2 H) 4.30 - 4.48 (m, 3 H) 2.35
- 2.45 (m, 1 H) 2.08 - 2.20 (m, 1 H) 1.89 - 1.99 (m, 2 H) 1.69 -
1.81 (m, 1 H) 1.49- 1.63 (m, 1 H) 48 ##STR00168## 479.1 (300 MHz)
10.07 (d, J = 8.71 Hz, 1 H) 8.60 (s, 1 H) 8.13 (d, J = 2.93 Hz, 1
H) 8.04 - 8.11 (m, 2 H) 5.18 - 5.28 (m, 1 H) 4.95 - 5.08 (m, 2 H)
4.63 (ddd, J = 10.34, 7.36, 3.12 Hz, 1 H) 4.36 - 4.51 (m, 3 H) 2.39
(br d, J = 10.64 Hz, 1 H) 2.11 - 2.20 (m, 1 H) 1.91 - 2.00 (m, 2 H)
1.75 (br d, J = 8.07 Hz, 1 H) 1.55 - 1.64 (m, 1 H) 49 ##STR00169##
441.1 (300 MHz) 9.12 (t, J = 5.00 Hz, 1 H) 8.62 (s, 1 H) 8.06 (d, J
= 2.93 Hz, 1 H) 8.00 (s, 1 H) 7.55 (dd, J = 8.67, 2.80 Hz, 1 H)
5.35 (dd, J = 14.81, 1.51 Hz, 1 H) 5.18 (t, J = 5.73 Hz, 1 H) 5.08
(t, J = 5.87 Hz, 1 H) 4.26 - 4.38 (m, 2 H) 4.10 - 4.17 (m, 1 H)
3.76 - 3.91 (m, 2 H) 3.63 - 3.72 (m, 1 H) 3.41 (ddd, J = 13.25,
6.14, 4.17 Hz, 1 H) 2.56 - 2.65 (m, 1 H) 2.14 - 2.28 (m, 1 H) 1.91
- 2.01 (m, 2 H) 1.63 - 1.86 (m, 2 H)
[0405] Biologic Assays
[0406] In-Vitro Assays
[0407] Materials and Methods
[0408] Biochemical Kinase Assay Method
[0409] The biochemical kinase assay was performed at Reaction
Biology Corporation (www.reactionbiology.com, Malvern, Pa.)
following the procedures described in the reference (Anastassiadis
T, et al Nat Biotechnol. 2011, 29, 1039). Specific kinase/substrate
pairs along with required cofactors were prepared in reaction
buffer; 20 mM Hepes pH 7.5, 10 mM MgCl.sub.2, 1 mM EGTA, 0.02%
Brij35, 0.02 mg/ml BSA, 0.1 mM Na.sub.3VO.sub.4, 2 mM DTT, 1% DMSO.
Compounds were delivered into the reaction, followed .about.20
minutes later by addition of a mixture of ATP (Sigma, St. Louis
Mo.) and .sup.33P ATP (Perkin Elmer, Waltham Mass.) to a final
concentration of 10 .mu.M. Reactions were carried out at room
temperature for 120 min, followed by spotting of the reactions onto
P81 ion exchange filter paper (Whatman Inc., Piscataway, N.J.).
Unbound phosphate was removed by extensive washing of filters in
0.75% phosphoric acid. After subtraction of background derived from
control reactions containing inactive enzyme, kinase activity data
was expressed as the percent remaining kinase activity in test
samples compared to vehicle (dimethyl sulfoxide) reactions.
IC.sub.50 values and curve fits were obtained using Prism (GraphPad
Software).
[0410] Cell Lines and Cell Culture:
[0411] Human medulla thyroid carcinoma cell line TT (containing RET
M918T mutation) and acute myelogenous cell line KG-1 were purchased
from ATCC. Human colon cancer cell line KM12 (containing TPM3-TRKA)
was obtained from NCI.
[0412] Cloning and Ba/F3 stable cell line creation
[0413] The EML4-ALK gene (variant 1) was synthesized at GenScript
and cloned into pCDH-CMV-MCS-EF1-Puro plasmid (System Biosciences,
Inc). Ba/F3-EML4-ALK wild type were generated by transducing Ba/F3
cells with lentivirus containing EML4-ALK wide type. Stable cell
lines were selected by puromycin treatment, followed by IL-3
withdrawal. Briefly, 5.times.10.sup.6 Ba/F3 cells were transduced
with lentivirus supernatant in the presence of 8 .mu.g/mL protamine
sulfate. The transduced cells were subsequently selected with 1
.mu.g/mL puromycin in the presence of IL3-containing medium
RPMI1640, plus 10% FBS. After 10-12 days of selection, the
surviving cells were further selected for IL3 independent
growth.
[0414] The KIF5B-RET gene was synthesized at GenScript and cloned
into pCDH-CMV-MCS-EF1-Puro plasmid (System Biosciences, Inc).
KIF5B-RET point mutation V804M was generated at GenScript by PCR
and confirmed by sequencing. Ba/F3-KIF5B-RET wild type and mutant
were generated by transducing Ba/F3 cells with lentivirus
containing KIF5B-RET wide type or mutant. Stable cell lines were
selected by puromycin treatment, followed by IL-3 withdrawal.
Briefly, 5.times.10.sup.6 Ba/F3 cells were transduced with
lentivirus supernatant in the presence of 8 .mu.g/mL protamine
sulfate. The transduced cells were subsequently selected with 1
.mu.g/mL puromycin in the presence of IL3-containing medium
RPM11640, plus 10% FBS. After 10-12 days of selection, the
surviving cells were further selected for IL3 independent
growth.
[0415] Cell Proliferation Assays:
[0416] Two thousand cells per well were seeded in 384 well white
plate for 24 hrs, and then treated with compounds for 72 hours
(37.degree. C., 5% CO.sub.2). Cell proliferation was measured using
CellTiter-Glo luciferase-based ATP detection assay (Promega)
following the manufactures's protocol. IC.sub.50 determinations
were performed using GraphPad Prism software (GraphPad, Inc., San
Diego, Calif.).
[0417] Immunoblotting for Cellular Kinase Phosphorylation
Assays
[0418] Half a million cells per well were seeded in 24 well plate
for 24 hrs, and then treated with compounds for 4 hours. Cells were
collected after treatment and lysed in RIPA buffer (50 mM Tris, pH
7.4, 150 mM NaCl, 1% NP-40, 0.5% Deoxycholate, 0.1% SDS)
supplemented with 10 mM EDTA, 1.times. Halt protease and
phosphatase inhibitors (Thermo Scientific). Protein lysates
(approximately 20 .mu.g) was resolved on 4-12% Bolt Bis-Tris
precasted gels with MES running buffer (Life Technologies),
transferred to nitrocellulose membranes using Trans-Blot Turbo
Transfer System (Bio-Rad) and detected with antibodies targeting
phosphorylated RET (Y905) (Cell Signaling Technology), total RET
(Cell Signaling Technology), actin (Cell Signaling Technology).
Antibodies were typically incubated overnight at 4.degree. C. with
gentle shake, followed by washes and incubation with the
appropriate HRP-conjugated secondary antibodies. Membranes were
incubated with chemiluminescent substrate for 5 min at room
temperature (SuperSignal West Femto, Thermo Scientific). The
chemiluminescent images were acquired with a C-DiGit Imaging System
(LI-COR Biosciences). The relative density of the chemiluminescent
bands were quantified via Image Studio Digits from LICOR. The half
inhibitory concentration (ICso) value is calculated using
non-linear regression analysis through GraphPad Prism software
(GraphPad, Inc., San Diego, Calif.).
[0419] Data and Results:
[0420] Enzymatic kinase activities of Compound 1 and 5.
TABLE-US-00008 IC.sub.50 (nM) at IC.sub.50 (nM) at 10 .mu.M ATP 10
.mu.M ATP Enzyme Compound 1 Compound 5 RET 0.0994 1.01 RET (A883F)
0.520 3.08 RET (E762Q) 2.07 0.58 RET (G691S) 3.01 0.941 RET (L790F)
0.120 1.31 RET (M918T) 0.114 1.42 RET (R749T) 0.271 0.32 RET
(R813Q) 0.341 2.46 RET (S891A) 0.664 0.303 RET (S904A) 0.159 1.22
RET (S904F) 0.0621 0.364 RET (V778I) <0.0508 0.233 RET (V804L)
10.0 2350 RET (V804M) 7.86 18.8 RET (Y791F) <0.0508 7.95 RET
(Y806H) 0.385 0.261 RET-CCDC6 (PTC1) 0.0893 1.97 RET-NC0A4 (PTC3)
0.0635 0.691 RET-PRKAR1A (PTC2) 0.129 0.29 Src 0.875 1.46 FYN 1.81
1.94 YES 1.72 2.64 HCK 1.95 2.71 LYN 1.97 2.03
[0421] Anti-Cell Proliferation Activity
TABLE-US-00009 TT cell BaF3 BaF3 KIF5B- BaF3 KIF5B- KM12 cell BaF3
KG-1 (RET C634W) KIF5B-RET RET_V804M RET_G810R (TPM3-TRKA) Cpd
EML4-ALK IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50
(nM) IC.sub.50 (nM) IC.sub.50 (nM) 1 211.4 131.2 <0.5 0.25 1002
30 3.0 2 >10000 5000 1784 1452 >10000 254.9 3 1500 505 7.9
<0.2 1704 4.2 4 3287 5000 461.9 184.4 5000 22 5 515.6 26.8 0.9
2.4 598 22 6.9 6 145.5 1 0.2 573.1 3 0.2 7 674.8 343.8 0.2 1845
99.2 37 8 4000 188.9 341.8 1928 0.3 9 8000 1000 2364 >10000 3.3
10 4000 78.3 274.4 1213 0.2 11 10000 307.3 838.9 3000 0.4 12 2709
159.9 100.5 4619 1014 13.8 13 5000 452 341.5 >10000 1121 28.4 14
907.8 273 120.3 10000 530 26.6 15 364.4 5.2 1.1 1245 8.7 5.1 16
340.5 47.4 16.6 5000 41.2 45.5 17 615.6 5 1.8 2731 10.7 4 18 77.2
16.9 7.1 1533 24.4 11.3 19 895.1 73.1 5.2 3073 78 7.8 20 1400 2.4
1.1 1855 7.8 0.5 21 461.7 86.9 -- <0.2 3459 82 13.8 22 157.5
155.8 -- <0.2 1763 127.6 49.3 23 1682 228.2 -- 98.9 3000 422.2
52.9 24 468.9 8.7 -- 1.8 1222 73.6 2.8 25 3000 677.3 -- 193.3 3000
559.1 277.3 26 1412 737.1 160 5000 323.2 210.1 27 1000 0.3 --
<0.2 2000 63 0.3 28 803.5 22.8 -- 1.5 2000 72 11.8 29 901 7.9 --
0.3 1377 133.7 1.7 30 2000 853.2 -- 161.9 337.2 1857 13.5 31 10000
10000 -- 4000 >10000 >10000 365 32 1056 223 -- 89 5718 500.8
20.2 33 2000 356.2 -- 197.9 4000 1196 124.5 34 1000 407.5 -- 62.2
10000 651.1 50 35 1105 55.7 -- 8.8 -- -- <0.2 36 >10000 10000
-- 8000 -- -- 1000 37 >10000 3000 -- 8000 -- -- 1201 38 82.1
<0.2 -- <0.2 349.3 0.3 <0.2 39 151.5 59.2 -- 10.2 3000
57.3 7.4 40 1951 19.1 -- <0.2 5000 1.8 <0.2 41 1448 389.2 --
5.1 -- 155.6 431.2 42 338.5 41 -- 0.5 -- 17.4 9.8 43 2991 359.4 --
68.9 -- 395.9 108.6 44 >10000 >10000 -- >10000 >10000
>10000 668.5 45 3109 1134 -- 525.7 5000 1712 202.4 46 55.5 5.9
-- <0.2 71.5 2.9 2.8 47 139.2 3.5 -- <0.2 469.3 3.6 <0.2
48 455.9 117 -- 0.2 1067 90.9 5.9 49 >10000 5238 -- 396.6 5000
1643 1457
[0422] Compound 5 Inhibited the Phosphorylation of RET
[0423] The pharmacodynamic inhibiting activity of Compound 5 on RET
in RET-driven cells was evaluated, and the results were shown in
FIGS. 1, 2 and 3. Compound 5 caused the suppression of RET
autophosphorylation at IC50s of around 0.3, 1-3 and 3-10 nM in TT,
Ba/F3 KIF5B-RET WT and Ba/F3 KIF5B-RET G810R respectively (FIGS.
1,2 & 3).
[0424] In Vivo Methods
[0425] Cell Lines
[0426] BaF3 KIF5B-RET WT and BaF3 KIF5B-RET G810R cells were
cultured using standard techniques in RPMI-1640 medium (Corning,
Inc) with 10% fetal bovine serum (Thermo Fisher Scientific, Inc) at
37.degree. C. in a humidified atmosphere with 5% CO.sub.2. TT cells
were cultured using standard techniques in F-12K medium (Corning,
Inc) with 10% fetal bovine serum (Thermo Fisher Scientific, Inc) at
37.degree. C. in a humidified atmosphere with 5% CO.sub.2. For
implantation, cells were harvested and pelleted by centrifugation
at 250 g for 2 minutes. Cells were washed once and resuspended in
serum-free medium supplemented with 50% matrigel (v/v).
[0427] Subcutaneous Xenograft Models in Immune Compromised Mice
[0428] For cell derived xenograft models, female SCID/Beige mice
(5-8 weeks of age) were obtained from Charles River Laboratory and
were housed in Innovive IVC disposable cages on HEPA filtered
ventilated racks with ad libitum access to rodent chow and water.
Five million cells in 100 .mu.L serum-free medium supplemented with
50% matrigel (Corning, Inc) were implanted subcutaneously in the
right flank region of the mouse. Tumor size and body weight were
measured on designated days. Tumor size was measured with an
electronic caliper and tumor volume was calculated as the product
of length*width.sup.2*0.5. Mice were randomized by tumor size into
treatment groups when tumor volume reached about 200 mm.sup.3 and
Compound 5 was administered orally (BID) at determined doses.
[0429] For PDX models, primary human tumor xenograft model LU2503
tumors were grown in stock mice. Tumor fragments (2-3 mm in
diameter) were harvested from stock mice an dinoculated into the
right front back of each female BALB/c nude mice for tumor
development. Tumor size and body weight were measured on designated
days. Tumor size was measured with an electronic caliper and tumor
volume was calculated as the product of length*width2*0.5. Mice
were randomized by tumor size into treatment groups when tumor
volume reached about 200 mm3 and Compound 5 was administered orally
(BID) at determined doses.
[0430] Antitumor Efficacy of Compound 5 in Xenograft Tumor
Models
[0431] The antitumor efficacy of Compound 5 was evaluated in
several tumor xenograft models representing cancer populations in
which dysregulation of RET is implicated.
[0432] TT Thyroid Medullary Carcinoma Model
[0433] The C634W mutation of RET in TT cells underlies the
molecular mechanism for tumor growth. SCID/Beige mice bearing TT
tumors (at the average tumor size of around 200 mm.sup.3) were
dosed with Compound 5 orally BID for 27 days (FIG. 4A). The control
group of mice were given vehicle only. Tumor volume (TMV) was
measured by caliper on the indicated days and is shown at
mean.+-.sem in FIG. 4A. The mean TMVs are significantly lower in
the treated groups compared to that of the control group
(p<0.0001) as determined by two-way repeated ANOVA followed by
post hoc analysis. Tumor growth inhibition (TGI) was calculated as
100%*{1-[(TMV.sub.Treated Last Day of Treatment-TMV.sub.Treated
First Day of Treatment)/(TMV.sub.Control on Last Day of
Treatment-TMV.sub.Control on First Day of Treatment)]} when
TMV.sub.Treated Last Day of Treatment>TMV.sub.Treated First Day
of Treatment. In the case of TMV.sub.Treated Last Day of
Treatment<TMV.sub.Treated First Day of Treatment, tumor
regression (REG) was calculated as 100%*(1-TMV.sub.Treated Last Day
of Treatment/TMV.sub.Treated First Day of Treatment). In this
study, Compound 5 demonstrated the ability to induce tumor
regression of 27% and 35% at the dose of 2 mg/kg BID and 5 mg/kg
BID, respectively. Tumor size was reduced in 10 out 10 mice treated
with Compound 5 at both dose levels. Body weight of the mice were
measured on the designated days of the mice as shown in FIG. 4B. No
body weight loss or overt abnormality was observed at either dose
levels.
[0434] Inhibition of the growth of BaF3 KIF5B-RET WT tumors and
BaF3 KIF5B-RET G810R tumors following oral administration of
Compound 5
[0435] In the BaF3 KIF5B-RET WT and BaF3 KIF5B-RET G810R xenograft
tumor models, the growth of tumor is presumably dependent on the
extopic RET activity. SCID/Beige mice bearing BaF3 KIF5B-RET WT
tumors (with average tumor size of .about.210 mm.sup.3) were dosed
with Compound 5 orally BID for 10 days (FIG. 5A). The control group
of mice were given vehicle only. Tumor volume (TMV) was measured by
caliper on the indicated days and is shown at mean.+-.sem in FIG.
5A. The mean TMVs are lower in the groups treated with compound 5
at 1 mg/kg BID (p>0.05) and 5 mg/kg BID (p<0.0001) compared
to that of the control group as determined by two-way repeated
ANOVA followed by post hoc analysis. Compound 5 demonstrated the
ability to inhibit tumor growth at 21% at the dose of 1 mg/kg BID.
Compound 5 treatment at 5 mg/kg BID resulted in a tumor regression
of 63%, with tumor size reduction in 9 out 10 mice. Body weight of
the mice were measured on the designated days of the mice as shown
in FIG. 5B. No body weight loss or overt abnormality was observed
in compound 5 treatment groups. SCID/Beige mice bearing BaF3
KIF5B-RET G810R tumors (with average tumor size of .about.170
mm.sup.3) were dosed with Compound 5 orally BID for 14 days (FIG.
6A). The control group of mice were given vehicle only. Tumor
volume (TMV) was measured by caliper on the indicated days and is
shown at mean.+-.sem in FIG. 6A. The mean TMVs are lower in the
groups treated with compound 5 at 1 mg/kg BID (p>0.05), 5 mg/kg
BID (p<0.0001) and 10 mg/kg BID (p<0.0001) compared to that
of the control group as determined by two-way ANOVA followed by
post hoc analysis. Compound 5 treatment at 1 mg/mg BID inhibited
tumor growth with a TGI of 22%. Compound 5 treatment at 5 mg/kg BID
resulted in a tumor regression of 39%, with tumor size reduction in
9 out 10 mice. Compound 5 treatment at 10 mg/kg BID resulted in
complete tumor regression in 9 out 9 mice. Body weight of the mice
were measured on the designated days of the mice as shown in FIG.
6B. No body weight loss or overt abnormality was observed in
compound 5 treatment groups during the treatment period.
[0436] CR1520 Patient Derived Xenograft (PDX) Colorectal Cancer
Model
[0437] The CR1520 is a PDX model derived from a colorectal cancer
patient harboring the NCOA4-RET fusion gene. Treating mice bearing
CR1520 tumors with Compound 5 at 1 mg/kg BID for 21 days resulted
inhibited tumor growth with a TGI of 63%, with tumors grew from 187
mm.sup.3 to 872 mm.sup.3. For comparison, the tumors grew from 187
mm.sup.3 to 2044 mm.sup.3 in the vehicle treated group (FIG. 7A).
Treating mice bearing CR1520 tumors with Compound 5 at 5 mg/kg BID
for 21 days resulted a tumor regression from 187 mm.sup.3 to 138
mm.sup.3, corresponding to a 26% tumor regression (FIG. 7A). No
body weight loss was observed after 21 days of BID treatment with
Compound 5 at 1 mg/kg BID or 5 mg/kg BID (FIG. 7B).
[0438] CTG-0838 Patient Derived Xenograft (PDX) NSCLC Model
[0439] The CTG-0838 is a PDX model derived from a non-small cell
lung cancer patient harboring the KIF5B-RET fusion gene. Treating
mice bearing CTG-0838 tumors with Compound 5 at 1 mg/kg BID and 2
mg/kg BID for 10 days resulted inhibited tumor growth with a TGI of
71% and 76%, respectively (FIG. 8A). Treating mice bearing CTG-0838
tumors with Compound 5 at 5 mg/kg BID for 10 days resulted a tumor
regression from 197 mm.sup.3 to 174 mm.sup.3, corresponding to a
12% tumor regression (FIG. 8A). No body weight loss was observed
after 10 days of BID treatment with Compound 5 at the 1, 2 or 5
mg/kg BID (FIG. 8B).
* * * * *